Compositions to improve the therapeutic benefit of suboptimally administered chemical compounds including substituted hexitols such as dianhydrogalactitol and diacetyldianhydrogalactitol

ABSTRACT

The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutic agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to substituted hexitols such as dianhydrogalactitol and diacetyldianhydrogalactitol.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part application and claims thebenefit of U.S. patent application Ser. No. 13/817,096 by Dennis M.Brown, Ph.D., filed Feb. 14, 2013, and entitled “Compositions andMethods to Improve the Therapeutic Benefit of Suboptimally AdministeredChemical Compounds Including Substituted Hexitols Such asDianhydrogalactitol and Diacetyldianhydrogalactitol,” which in turn wasa national stage and claimed the benefit of PCT Patent Application Ser.No. PCT/US2011/048031 by Dennis M. Brown, Ph.D., filed Aug. 7, 2011,which in turn claimed the benefit of: (1) U.S. Provisional ApplicationSer. No. 61/401,705 by Dennis M. Brown, Ph.D., filed Aug. 18, 2010, andentitled “Compositions and Methods to Improve the Therapeutic Benefit ofSuboptimally Administered Chemical Compounds Including SubstitutedHexitols Such as Dianhydrogalactitol for the Treatment of Benign andNeoplastic Hyperproliferative Disease Conditions”; (2) U.S. ProvisionalApplication Ser. No. 61/401,706 by Dennis M. Brown, Ph.D., filed Aug.18, 2010, and entitled “Compositions and Methods to Improve theTherapeutic Benefit of Suboptimally Administered Chemical CompoundsIncluding Substituted Hexitols Such as Diacetyldianhydrogalactitol forthe Treatment of Benign and Neoplastic Hyperproliferative DiseaseConditions”; (3) U.S. Provisional Application Ser. No. 61/401,707 byDennis M. Brown, Ph.D., filed Aug. 18, 2010, and entitled “Compositionsand Methods to Improve the Therapeutic Benefit of SuboptimallyAdministered Chemical Compounds Including Substituted Hexitols Such asDiacetyldianhydrogalactitol for the Condition of Benign and NeoplasticHyperproliferative Conditions”; (4) U.S. Provisional Application Ser.No. 61/401,709 by Dennis M. Brown, Ph.D., filed Aug. 18, 2010, andentitled “Compositions and Methods to Improve the Therapeutic Benefit ofSuboptimally Administered Chemical Compounds Including SubstitutedHexitols Such as Diacetyldianhydrogalactitol for the Condition of Benignand Neoplastic Hyperproliferative Conditions”; and (5) U.S. ProvisionalApplication Ser. No. 61/401,712 by Dennis M. Brown, Ph.D., filed Aug.18, 2010, and entitled “Compositions and Methods to Improve theTherapeutic Benefit of Suboptimally Administered Chemical CompoundsIncluding Substituted Hexitols Such as Diacetyldianhydrogalactitol forthe Condition of Benign and Neoplastic Hyperproliferative Conditions.”All the above-mentioned applications are incorporated herein in theirentirety by this reference.

FIELD OF THE INVENTION

The present invention relates to the general field of hyperproliferativediseases including oncology with a focus on novel methods andcompositions for the improved utility of chemical agents, compounds, anddosage forms previously limited by suboptimal human therapeuticperformance including substituted hexitols such as dianhydrogalactitoland diacetyldianhydrogalactitol, as well as other classes of chemicalagents.

BACKGROUND OF THE INVENTION

The search for and identification of cures for many life-threateningdiseases that plague humans still remains an empirical and sometimesserendipitous process. While many advances have been made from basicscientific research to improvements in practical patient management,there still remains tremendous frustration in the rational andsuccessful discovery of useful therapies particularly forlife-threatening diseases such as cancer, inflammatory conditions,infection, and other conditions.

Since the “War on Cancer” began in the early 1970's by the United StatesNational Cancer Institute (NCI) of the National Institutes of Health(NIH), a wide variety of strategies and programs have been created andimplemented to prevent, diagnose, treat and cure cancer. One of theoldest and arguably most successful programs has been the synthesis andscreening of small chemical entities (<1500 MW) for biological activityagainst cancer. This program was organized to improve and streamline theprogression of events from chemical synthesis and biological screeningto preclinical studies for the logical progression into human clinicaltrials with the hope of finding cures for the many types oflife-threatening malignant tumors. The synthesis and screening ofhundreds of thousands of chemical compounds from academic and industrialsources, in addition to the screening of natural products and extractsfrom prokaryotes, invertebrate animals, plant collections, and othersources from all over the world has been and continues to be a majorapproach for the identification of novel lead structures as potentialnew and useful medicines. This is in addition to other programsincluding biotherapeutics designed to stimulate the human immune systemwith vaccines, therapeutic antibodies, cytokines, lymphokines,inhibitors of tumor blood vessel development (angiogenesis) or gene andantisense therapies to alter the genetic make-up of cancer cells, andother biological response modifiers.

The work supported by the NCI, other governmental agencies both domesticand foreign in academic or industrial research and developmentlaboratories has resulted in an extraordinary body of biological,chemical and clinical information. In addition, large chemical librarieshave been created, as well as highly characterized in vitro and in vivobiological screening systems that have been successfully used. However,from the tens of billions of dollars spent over the past thirty yearssupporting these programs both preclinically and clinically, only asmall number of compounds have been identified or discovered that haveresulted in the successful development of useful therapeutic products.Nevertheless, the biological systems both in vitro and in vivo and the“decision trees” used to warrant further animal studies leading toclinical studies have been validated. These programs, biological models,clinical trial protocols, and other information developed by this workremain critical for the discovery and development of any new therapeuticagent.

Unfortunately, many of the compounds that have successfully met thepreclinical testing and federal regulatory requirements for clinicalevaluation were either unsuccessful or disappointing in human clinicaltrials. Many compounds were found to have untoward or idiosyncraticside-effects that were discovered during human clinical Phase Idose-escalation studies used to determine the maximum tolerated dose(MTD) and side-effect profile. In some cases, these toxicities or themagnitude of their toxicity were not identified or predicted inpreclinical toxicology studies. In other cases, chemical agents where invitro and in vivo studies suggested a potentially unique activityagainst a particular tumor type, molecular target or biological pathwaywere not successful in human Phase II clinical trials where specificexamination of particular cancer indications/types were evaluated ingovernment sanctioned (e.g., U.S. FDA), IRB approved clinical trials. Inaddition, there are those cases where potential new agents wereevaluated in randomized Phase III clinical trials where a significantclinical benefit could not be demonstrated; such cases have also beenthe cause of great frustration and disappointment. Finally, a number ofcompounds have reached commercialization but their ultimate clinicalutility has been limited by poor efficacy as monotherapy (<25% responserates) and untoward dose-limiting side-effects (Grade III and IV) (e.g.,myelosuppression, neurotoxicity, cardiotoxicity, gastrointestinaltoxicities, or other significant side effects).

In many cases, after the great time and expense of developing and movingan investigational compound into human clinical trials and whereclinical failure has occurred, the tendency has been to return to thelaboratory to create a better analog, look for agents with differentstructures but potentially related mechanisms of action, or try othermodifications of the drug. In some cases, efforts have been made to tryadditional Phase I or II clinical trials in an attempt to make someimprovement with the side-effect profile or therapeutic effect inselected patients or cancer indications. In many of those cases, theresults did not realize a significant enough improvement to warrantfurther clinical development toward product registration. Even forcommercialized products, their ultimate use is still limited bysuboptimal performance.

With so few therapeutics approved for cancer patients and therealization that cancer is a collection of diseases with a multitude ofetiologies and that a patient's response and survival from therapeuticintervention is complex with many factors playing a role in the successor failure of treatment including disease indication, stage of invasionand metastatic spread, patient gender, age, health conditions, previoustherapies or other illnesses, genetic markers that can either promote orretard therapeutic efficacy, and other factors, the opportunity forcures in the near term remains elusive. Moreover, the incidence ofcancer continues to rise with an approximate 4% increase predicted for2003 in the United States by the American Cancer Society such that over1.3 million new cancer cases are estimated. In addition, with advancesin diagnosis such as mammography for breast cancer and PSA tests forprostate cancer, more patients are being diagnosed at a younger age. Fordifficult to treat cancers, a patient's treatment options are oftenexhausted quickly resulting in a desperate need for additional treatmentregimens. Even for the most limited of patient populations, anyadditional treatment opportunities would be of considerable value. Thisinvention focuses on inventive compositions and methods for improvingthe therapeutic benefit of suboptimally administered chemical compoundsincluding substituted hexitols such as dianhydrogalactitol.

Relevant literature includes Foye, W. O., “Cancer ChemotherapeuticAgents,” American Chemical Society, 1995, and Dorr, R. T., and Von Hoff,D. D., “Cancer Chemotherapy Handbook,” Appleton and Lange, 1994.

Therefore, there is a need for compositions and methods that improve thetherapeutic benefit of suboptimally administered chemical compounds andtherapeutic compositions.

SUMMARY OF THE INVENTION

This invention meets the needs described above for compositions andmethods that improve the therapeutic benefit of suboptimallyadministered chemical compounds and therapeutic compositions.Specifically, this invention relates to novel compositions and methodsto improve the utility of chemical agents with suboptimal performance inpatients suffering with cancer. The invention describes novelimprovements, pharmaceutical ingredients, dosage forms, excipients,solvents, diluents, drug delivery systems, preservatives, more accuratedrug administrations, improved dose determination and schedules,toxicity monitoring and ameliorization, techniques or agents tocircumvent or reduce toxicity, techniques and tools to identify/predictthose patients who might have a better outcome with a therapeutic agentby the use of phenotype or genotype determination through the use ofdiagnostic kits or pharmacokinetic or metabolism monitoring approaches.The invention also relates to the use of drug delivery systems, novelprodrugs, polymer conjugates, novel routes of administration, otheragents to potentiate the activity of the compounds or inhibit the repairof suboptimal cellular effects or sublethal damage or to “push” the cellinto more destructive cellular phases such as apoptosis. In some case,the use of these suboptimal therapeutics in conjunction with radiationor other conventional chemotherapeutic agents or biotherapeutic agentssuch as antibodies, vaccines, cytokines, lymphokines, gene and antisensetherapies, or other chemotherapeutic or biotherapeutic agents, wouldprovide novel approaches and significant improvement.

In the inventive compositions and methods, the term suboptimal therapyincludes agents where Phase I toxicity precluded further human clinicalevaluation. It also includes those agents from Phase II trials wherelimited (<25% response rates) or no significant tumor responses wereidentified. Also, suboptimal therapy includes those agents, the subjectof Phase III clinical trials the outcome of which was either medicallyor statistically not significant to warrant regulatory submission orapproval by government agencies for commercialization or commercializedagents whose clinical performance (i.e. response rates) as a monotherapyare less than 25%, or whose side-effects are severe enough to limit wideutility. Agents with suboptimal clinical activity include but are notlimited to the following: substituted hexitols such asdianhydrogalactitol and diacetyldianhydrogalactitol, Avastin(bevacizumab), Rituxan (rituximab), Nexavar (sorafenib), dasatinib,nilotinib, Provenge (sipuleucel-T), Tarceva (erlotinib), and Iressa(gefitinib). More specifically, the inventive methods and compositionsalso focus on improvements for substituted hexitols includingdianhydrogalactitol and diacetyldianhydrogalactitol.

One aspect of the invention is a method to improve the efficacy and/orreduce the side effects of suboptimally administered drug therapycomprising the steps of:

(i) identifying at least one factor or parameter associated with theefficacy and/or occurrence of side effects of the drug therapy; and

(ii) modifying the factor or parameter to improve the efficacy and/orreduce the side effects of the drug therapy.

In this method, the factor or parameter can be selected from the groupconsisting of:

(i) dose modification;

(ii) route of administration;

(iii) schedule of administration;

(iv) indications for use;

(v) selection of disease stage;

(vi) other indications;

(vii) patient selection;

(viii) patient/disease phenotype;

(ix) patient/disease genotype;

(x) pre/post-treatment preparation

(xi) toxicity management;

(xii) pharmacokinetic/pharmacodynamic monitoring;

(xiii) drug combinations;

(xiv) chemosensitization;

(xv) chemopotentiation;

(xvi) post-treatment patient management;

(xvii) alternative medicine/therapeutic support;

(xviii) bulk drug product improvements;

(xix) diluent systems;

(xx) solvent systems;

(xxi) excipients;

(xxii) dosage forms;

(xxiii) dosage kits and packaging;

(xxiv) drug delivery systems;

(xxv) drug conjugate forms;

(xxvi) compound analogs;

(xxvii) prodrugs;

(xxvii) multiple drug systems;

(xxviii) biotherapeutic enhancement;

(xxix) biotherapeutic resistance modulation;

(xxx) radiation therapy enhancement;

(xxxi) novel mechanisms of action; and

(xxxii) selective target cell population therapeutics.

The drug therapy can be administered to treat a hyperproliferativedisease, such as cancer.

Typically, the suboptimally administered drug therapy comprisesadministration of a substituted hexitol. In one alternative, preferably,the substituted hexitol is selected from the group consisting ofdianhydrogalactitol and a derivative thereof. In this alternative, morepreferably, the substituted hexitol is dianhydrogalactitol. In anotheralternative, preferably, the substituted hexitol is selected from thegroup consisting of diacetyldianhydrogalactitol and a derivativethereof. In this alternative, more preferably, the substituted hexitolis diacetyldianhydrogalactitol.

In yet another alternative, the suboptimally administered drug therapycomprises administration of a therapeutic agent selected from the groupconsisting of Avastin (bevacizumab), Rituxan (rituximab), Nexavar(sorafenib), dasatinib, nilotinib, Provenge (sipuleucel-T), Tarceva(erlotinib), and Iressa (gefitinib).

The following alternatives describe the use of dianhydrogalactitol,diacetyldianhydrogalactitol, or, in some cases as set forth below, aderivative of either dianhydrogalactitol or diacetyldianhydrogalactitol,together with a modification of a factor or parameter as described aboveto improve the efficacy and/or reduce the side effects of the drugtherapy.

When the improvement is made by dose modification, the dose modificationcan be a modification selected from the group consisting of:

-   -   (a) continuous i.v. infusion for hours to days;    -   (b) biweekly administration;    -   (c) doses greater than 5 mg/m²/day;    -   (d) progressive escalation of dosing from 1 mg/m²/day based on        patient tolerance;    -   (e) use of caffeine to modulate metabolism;    -   (f) use of isonazid to modulate metabolism;    -   (g) selected and intermittent boosting of dosage administration;    -   (h) administration of single and multiple doses escalating from        5 mg/m²/day via bolus;    -   (i) oral dosages of below 30 mg/m²; and    -   (j) oral dosages of above 130 mg/m².

When the improvement is made by the route of administration, the routeof administration can be a route of administration selected from thegroup consisting of:

-   -   (a) topical administration;    -   (b) intravesicular administration for bladder cancer;    -   (c) oral administration;    -   (d) slow release oral delivery;    -   (e) intrathecal administration;    -   (f) intraarterial administration;    -   (g) continuous infusion; and    -   (h) intermittent infusion.

When the improvement is made by the schedule of administration, theschedule of administration can be a schedule of administration selectedfrom the group consisting of:

-   -   (a) daily administration;    -   (b) weekly administration;    -   (c) weekly administration for three weeks;    -   (d) biweekly administration;    -   (e) biweekly administration for three weeks with a 1-2 week rest        period;    -   (f) intermittent boost dose administration; and    -   (g) daily administration for one week for multiple weeks.

When the improvement is made by the indication for use, the indicationfor use can be an indication for use selected from the group consistingof:

-   -   (a) use for treatment of leukemias;    -   (b) use for treatment of myelodysplastic syndrome;    -   (c) use for treatment of angiogenic diseases;    -   (d) use for treatment of benign prostatic hyperplasia;    -   (e) use for treatment of psoriasis;    -   (f) use for treatment of gout;    -   (g) use for treatment of transplantation rejections;    -   (h) use for prevention of restenosis in cardiovascular disease;    -   (i) use for treatment of mycosis fungoides;    -   (j) use in bone marrow transplantation;    -   (k) use as an anti-infective agent;    -   (l) use for treatment of AIDS; and    -   (m) use for treatment of lymphoma.

When the improvement is made by selection of disease stage, theselection of disease stage can be selected from the group consisting of:

-   -   (a) use for the treatment of localized polyp stage colon cancer;    -   (b) use for leukoplakia in the oral cavity;    -   (c) use for angiogenesis inhibition to prevent or limit        metastatic spread of a malignancy; and    -   (d) use for treatment of HIV with a therapy selected from the        group consisting of azidothymidine (AZT), dideoxyadenosine        (DDI), and reverse transcriptase inhibitors.

When the improvement is made by other indications, the other indicationscan be selected from the group consisting of:

-   -   (a) use as an anti-infective agent;    -   (b) use as an antiviral agent;    -   (c) use as an antibacterial agent;    -   (d) use as an agent to treat pleural effusion;    -   (e) use as an antifungal agent;    -   (f) use as an anti-parasitic agent;    -   (g) use as an agent to treat eczema;    -   (h) use as an agent to treat herpes zoster (shingles);    -   (i) use as an agent to treat condylomata;    -   (j) use as an agent to treat HPV; and    -   (k) use as an agent to treat HSV.

When the improvement is made by patient selection, the patient selectioncan be carried out by a criterion selected from the group consisting of:

-   -   (a) selecting patients with a disease condition characterized by        a high level of a metabolic enzyme selected from the group        consisting of histone deacetylase and ornithine decarboxylase;    -   (b) selecting patients with a low or high susceptibility to a        condition selected from the group consisting of thrombocytopenia        and neutropenia;    -   (c) selecting patients intolerant of GI toxicities; and    -   (d) selecting patients characterized by over- or        under-expression of a gene selected from the group consisting of        c-Jun, a GPCR, a signal transduction protein, VEGF, a        prostate-specific gene, and a protein kinase.

Where the improvement is made by analysis of patient or diseasephenotype, the analysis of patient or disease phenotype can be carriedout by a method selected from the group consisting of:

-   -   (i) use of a diagnostic tool, a diagnostic technique, a        diagnostic kit, or a diagnostic assay to confirm a patient's        particular phenotype;    -   (ii) use of a method for measurement of a marker selected from        the group consisting of histone deacetylase, ornithine        decarboxylase, VEGF, a protein that is a gene product of a        prostate specific gene, a protein that is a gene product of jun,        a protein kinase, quantity or activity of MGMT, methylation of        MGMT promoter, and mutant isocitrate dehydrogenase (IDH);    -   (iii) surrogate compound dosing; and    -   (iv) low dose pre-testing for enzymatic status.

When the improvement is made by analysis of patient or disease genotype,the analysis of patient or disease genotype can be carried out by amethod selected from the group consisting of:

-   -   (a) use of a diagnostic tool, a diagnostic technique, a        diagnostic kit, or a diagnostic assay to confirm a patient's        particular genotype;    -   (b) use of a gene chip;    -   (c) use of gene expression analysis;    -   (d) use of single nucleotide polymorphism (SNP) analysis; and    -   (e) measurement of the level of a metabolite or a metabolic        enzyme.

When the improvement is made by pre/post treatment preparation, thepre/post treatment preparation can be selected from the group consistingof:

-   -   (a) the use of colchicine or an analog thereof;    -   (b) the use of a uricosuric;    -   (c) the use of uricase;    -   (d) the non-oral use of nicotinamide;    -   (e) the use of a sustained-release form of nicotinamide;    -   (f) the use of an inhibitor of poly-ADP ribose polymerase;    -   (g) the use of caffeine;    -   (h) the use of leucovorin rescue;    -   (i) infection control; and    -   (j) the use of an anti-hypertensive agent.

When the improvement is made by toxicity management, the toxicitymanagement can be selected from the group consisting of:

-   -   (a) the use of colchicine or an analog thereof;    -   (b) the use of a uricosuric;    -   (c) the use of uricase;    -   (d) the non-oral use of nicotinamide;    -   (e) the use of a sustained-release form of nicotinamide;    -   (f) the use of an inhibitor of poly-ADP ribose polymerase;    -   (g) the use of caffeine;    -   (h) the use of leucovorin rescue;    -   (i) the use of sustained-release allopurinol;    -   (j) the non-oral use of allopurinol;    -   (k) the use of bone marrow transplants;    -   (l) the use of a blood cell stimulant;    -   (m) the use of blood or platelet infusions;    -   (n) the administration of an agent selected from the group        consisting of filgrastim (Neupogen®), G-CSF, and GM-CSF;    -   (o) the application of a pain management technique;    -   (p) the administration of an anti-inflammatory agent;    -   (q) the administration of fluids;    -   (r) the administration of a corticosteroid;    -   (s) the administration of an insulin control medication;    -   (t) the administration of an antipyretic;    -   (u) the administration of an anti-nausea treatment;    -   (v) the administration of an anti-diarrheal treatment;    -   (w) the administration of N-acetylcysteine; and    -   (x) the administration of an antihistamine.

When the improvement is made by pharmacokinetic/pharmacodynamicmonitoring, the pharmacokinetic/pharmacodynamic monitoring can beperformed by a method selected from the group consisting of:

-   -   (a) multiple determinations of blood plasma levels; and    -   (b) multiple determinations of at least one metabolite in blood        or urine.

When the improvement is made by drug combination, the drug combinationcan be selected from the group consisting of:

-   -   (a) use with topoisomerase inhibitors;    -   (b) use with fraudulent nucleosides;    -   (c) use with fraudulent nucleotides;    -   (d) use with thymidylate synthetase inhibitors;    -   (e) use with signal transduction inhibitors;    -   (f) use with cisplatin or platinum analogs;    -   (g) use with alkylating agents;    -   (h) use with anti-tubulin agents;    -   (i) use with antimetabolites;    -   (j) use with berberine;    -   (k) use with apigenin;    -   (l) use with amonafide;    -   (m) use with vinca alkaloids;    -   (n) use with 5-fluorouracil;    -   (o) use with curcumin;    -   (p) use with NF-κB inhibitors;    -   (q) use with rosmarinic acid;    -   (r) use with mitoguazone;    -   (s) use with tetrandrine;    -   (t) use with an inhibitor of mutant isocitrate dehydrogenase        (IDH);    -   (u) use with a MGMT inhibitor; and    -   (v) use with an agent that inhibits NF-κB-enhanced expression of        MGMT.

When the improvement is made by chemosensitization, thechemosensitization can comprise the use of dianhydrogalactitol as achemosensitizer in combination with an agent selected from the groupconsisting of:

-   -   (a) topoisomerase inhibitors;    -   (b) fraudulent nucleosides;    -   (c) fraudulent nucleotides;    -   (d) thymidylate synthetase inhibitors;    -   (e) signal transduction inhibitors;    -   (f) cisplatin or platinum analogs;    -   (g) alkylating agents;    -   (h) anti-tubulin agents;    -   (i) antimetabolites;    -   (j) berberine;    -   (k) apigenin;    -   (l) amonafide;    -   (m) vinca alkaloids;    -   (n) 5-fluorouracil;    -   (o) curcumin;    -   (p) NF-κB inhibitors;    -   (q) rosmarinic acid;    -   (r) mitoguazone; and    -   (s) tetrandrine.

When the improvement is made by chemopotentiation, the chemopotentiationcan comprise the use of dianhydrogalactitol as a chemopotentiator incombination with an agent selected from the group consisting of:

-   -   (a) topoisomerase inhibitors;    -   (b) fraudulent nucleosides;    -   (c) fraudulent nucleotides;    -   (d) thymidylate synthetase inhibitors;    -   (e) signal transduction inhibitors;    -   (f) cisplatin or platinum analogs;    -   (g) alkylating agents;    -   (h) anti-tubulin agents;    -   (i) antimetabolites;    -   (j) berberine;    -   (k) apigenin;    -   (l) amonafide;    -   (m) vinca alkaloids;    -   (n) 5-fluorouracil;    -   (o) curcumin;    -   (p) NF-κB inhibitors;    -   (q) rosmarinic acid;    -   (r) mitoguazone; and    -   (s) tetrandrine.

When the improvement is made by post-treatment management, thepost-treatment management can be selected from the group consisting of:

-   -   (a) a therapy associated with pain management;    -   (b) administration of an anti-emetic;    -   (c) an anti-nausea therapy;    -   (d) administration of an anti-inflammatory agent;    -   (e) administration of an anti-pyretic agent; and    -   (f) administration of an immune stimulant.

When the improvement is made by alternative medicine/therapeuticsupport, the alternative medicine/therapeutic support can be selectedfrom the group consisting of:

-   -   (a) hypnosis;    -   (b) acupuncture;    -   (c) meditation;    -   (d) a herbal medication created either synthetically or through        extraction; and    -   (e) applied kinesiology.

When the improvement is made by a bulk drug product improvement, thebulk drug product improvement can be selected from the group consistingof:

-   -   (a) salt formation;    -   (b) preparation as a homogeneous crystal structure;    -   (c) preparation as a pure isomer;    -   (d) increased purity;    -   (e) preparation with lower residual solvent content; and    -   (f) preparation with lower residual heavy metal content.

When the improvement is made by use of a diluent, the diluent can beselected from the group consisting of:

-   -   (a) an emulsion;    -   (b) dimethylsulfoxide (DMSO);    -   (c) N-methylformamide (NMF)    -   (d) DMF;    -   (e) ethanol;    -   (f) benzyl alcohol;    -   (g) dextrose-containing water for injection;    -   (h) Cremophor;    -   (i) cyclodextrin; and    -   (j) PEG.

When the improvement is made by a solvent system, the solvent system canbe selected from the group consisting of:

-   -   (a) an emulsion;    -   (b) dimethylsulfoxide (DMSO);    -   (c) N-methylformamide (NMF)    -   (d) DMF;    -   (e) ethanol;    -   (f) benzyl alcohol;    -   (g) dextrose-containing water for injection;    -   (h) Cremophor;    -   (i) cyclodextrin; and    -   (j) PEG.

When the improvement is made by use of an excipient, the excipient canbe selected from the group consisting of:

-   -   (a) mannitol;    -   (b) albumin;    -   (c) EDTA;    -   (d) sodium bisulfite;    -   (e) benzyl alcohol;    -   (f) a carbonate buffer; and    -   (g) a phosphate buffer.

When the improvement is made by use of a dosage form, the dosage formcan be selected from the group consisting of:

-   -   (a) tablets;    -   (b) capsules;    -   (c) topical gels;    -   (d) topical creams;    -   (e) patches;    -   (f) suppositories; and    -   (g) lyophilized dosage fills.

When the improvement is made by use of dosage kits and packaging, thedosage kits and packaging can be selected from the group consisting ofthe use of amber vials to protect from light and the use of stopperswith specialized coatings to improve shelf-life stability.

When the improvement is made by use of a drug delivery system, the drugdelivery system can be selected from the group consisting of:

-   -   (a) nanocrystals;    -   (b) bioerodible polymers;    -   (c) liposomes;    -   (d) slow release injectable gels; and    -   (e) microspheres.

When the improvement is made by use of a drug conjugate form, the drugconjugate form can be selected from the group consisting of:

-   -   (a) a polymer system;    -   (b) polylactides;    -   (c) polyglycolides;    -   (d) amino acids;    -   (e) peptides; and    -   (f) multivalent linkers.

When the improvement is made by use of a compound analog, the compoundanalog can be selected from the group consisting of:

-   -   (a) alteration of side chains to increase or decrease        lipophilicity;    -   (b) addition of an additional chemical functionality to alter a        property selected from the group consisting of reactivity,        electron affinity, and binding capacity; and    -   (c) alteration of salt form.

When the improvement is made by use of a prodrug system, the prodrug canbe selected from the group consisting of:

-   -   (a) the use of enzyme sensitive esters;    -   (b) the use of dimers;    -   (c) the use of Schiff bases;    -   (d) the use of pyridoxal complexes; and    -   (e) the use of caffeine complexes.

When the improvement is made by use of a multiple drug system, themultiple drug system can employ a mechanism selected from the groupconsisting of:

-   -   (a) use of multi-drug resistance inhibitors;    -   (b) use of specific drug resistance inhibitors;    -   (c) use of specific inhibitors of selective enzymes;    -   (d) use of signal transduction inhibitors;    -   (e) use of repair inhibition; and    -   (f) use of topoisomerase inhibitors with non-overlapping side        effects.

When the improvement is made by use of biotherapeutic enhancement, thebiotherapeutic enhancement can be performed by use in combination assensitizers/potentiators with a therapeutic agent or technique selectedfrom the group consisting of:

-   -   (a) cytokines;    -   (b) lymphokines;    -   (c) therapeutic antibodies;    -   (d) antisense therapies;    -   (e) gene therapies;    -   (f) ribozymes; and    -   (g) RNA interference.

When the improvement is made by use of biotherapeutic resistancemodulation, the biotherapeutic resistance modulation can comprise useagainst tumors resistant to a therapeutic agent or technique selectedfrom the group consisting of:

-   -   (a) biological response modifiers;    -   (b) cytokines;    -   (c) lymphokines;    -   (d) therapeutic antibodies;    -   (e) antisense therapies;    -   (f) gene therapies;    -   (g) ribozymes; and    -   (h) RNA interference.

When the improvement is made by use of radiation therapy enhancement,the radiation therapy enhancement can be performed by use of an agent ortechnique selected from the group consisting of:

-   -   (a) hypoxic cell sensitizers;    -   (b) radiation sensitizers/protectors;    -   (c) photosensitizers;    -   (d) radiation repair inhibitors;    -   (e) thiol depleters;    -   (f) vaso-targeted agents;    -   (g) DNA repair inhibitors;    -   (h) radioactive seeds;    -   (i) radionuclides;    -   (j) radiolabeled antibodies; and    -   (k) brachytherapy.

When the improvement is made by use of novel mechanisms of action, thenovel mechanism of action can be a therapeutic interaction with a targetor mechanism selected from the group consisting of:

-   -   (a) inhibitors of poly-ADP ribose polymerase;    -   (b) agents that affect vasculature or vasodilation;    -   (c) oncogenic targeted agents;    -   (d) signal transduction inhibitors;    -   (e) EGFR inhibition;    -   (f) protein kinase C inhibition;    -   (g) phospholipase C downregulation;    -   (h) Jun downregulation;    -   (i) histone genes;    -   (j) VEGF;    -   (k) ornithine decarboxylase;    -   (l) ubiquitin C;    -   (m) jun D;    -   (n) v-jun;    -   (o) GPCRs;    -   (p) protein kinase A;    -   (q) protein kinases other than protein kinase A;    -   (r) prostate specific genes;    -   (s) telomerase; and    -   (t) histone deacetylase.

When the improvement is made by use of selective target cell populationtherapeutics, the use of selective target cell population therapeuticscan be a use selected from the group consisting of:

-   -   (a) use against radiation sensitive cells;    -   (b) use against radiation resistant cells;    -   (c) use against energy depleted cells; and    -   (d) use against endothelial cells.

Another aspect of the present invention is a composition to improve theefficacy and/or reduce the side effects of suboptimally administereddrug therapy comprising an alternative selected from the groupconsisting of:

-   -   (i) a therapeutically effective quantity of a modified        therapeutic agent or a derivative, analog, or prodrug of a        therapeutic agent or modified therapeutic agent, wherein the        modified therapeutic agent or the derivative, analog or prodrug        of the therapeutic agent or modified therapeutic agent possesses        increased therapeutic efficacy or reduced side effects as        compared with an unmodified therapeutic agent;    -   (ii) a composition comprising:        -   (a) a therapeutically effective quantity of a therapeutic            agent, a modified therapeutic agent or a derivative, analog,            or prodrug of a therapeutic agent or modified therapeutic            agent; and        -   (b) at least one additional therapeutic agent, therapeutic            agent subject to chemosensitization, therapeutic agent            subject to chemopotentiation, diluent, excipient, solvent            system, or drug delivery system, wherein the composition            possesses increased therapeutic efficacy or reduced side            effects as compared with an unmodified therapeutic agent;    -   (iii) a therapeutically effective quantity of a therapeutic        agent, a modified therapeutic agent, or a derivative, analog, or        prodrug of a therapeutic agent or modified therapeutic agent        that is incorporated into a dosage form, wherein the therapeutic        agent, the modified therapeutic agent, or the derivative,        analog, or prodrug of a therapeutic agent or modified        therapeutic agent incorporated into the dosage form possesses        increased therapeutic efficacy or reduced side effects as        compared with an unmodified therapeutic agent;    -   (iv) a therapeutically effective quantity of a therapeutic        agent, a modified therapeutic agent, or a derivative, analog, or        prodrug of a therapeutic agent or modified therapeutic agent        that is incorporated into a dosage kit and packaging, wherein        the therapeutic agent, the modified therapeutic agent, or the        derivative, analog, or prodrug of a therapeutic agent or        modified therapeutic agent incorporated into the dosage kit and        packaging possesses increased therapeutic efficacy or reduced        side effects as compared with an unmodified therapeutic agent;        and    -   (v) a therapeutically effective quantity of a therapeutic agent,        a modified therapeutic agent, or a derivative, analog, or        prodrug of a therapeutic agent or modified therapeutic agent        that is subjected to a bulk drug product improvement, wherein        the therapeutic agent, the modified therapeutic agent, or the        derivative, analog, or prodrug of a therapeutic agent or        modified therapeutic agent subject to the bulk drug product        improvement possesses increased therapeutic efficacy or reduced        side effects as compared with an unmodified therapeutic agent.

Typically, the composition possesses increased efficacy or reduced sideeffects for cancer therapy. Typically, the unmodified therapeutic agentis dianhydrogalactitol or diacetyldianhydrogalactitol.

In one alternative of a composition according to the present invention,the composition can comprise a drug combination comprising:

-   -   (i) dianhydrogalactitol; and    -   (ii) an additional therapeutic agent selected from the group        consisting of:        -   (a) topoisomerase inhibitors;        -   (b) fraudulent nucleosides;        -   (c) fraudulent nucleotides;        -   (d) thymidylate synthetase inhibitors;        -   (e) signal transduction inhibitors;        -   (f) cisplatin or platinum analogs;        -   (g) alkylating agents;        -   (h) anti-tubulin agents;        -   (i) antimetabolites;        -   (j) berberine;        -   (k) apigenin;        -   (l) amonafide;        -   (m) vinca alkaloids;        -   (n) 5-fluorouracil;        -   (o) curcumin;        -   (p) NF-κB inhibitors;        -   (q) rosmarinic acid;        -   (r) mitoguazone;        -   (s) tetrandrine;        -   (t) an inhibitor of mutant isocitrate dehydrogenase (IDH);        -   (u) a MGMT inhibitor; and        -   (v) an agent that inhibits NF-κB-enhanced expression of            MGMT.

In another alternative of a composition according to the presentinvention, the composition can comprise a drug combination comprising:

-   -   (i) diacetyldianhydrogalactitol; and    -   (ii) an additional therapeutic agent selected from the group        consisting of:        -   (a) topoisomerase inhibitors;        -   (b) fraudulent nucleosides;        -   (c) fraudulent nucleotides;        -   (d) thymidylate synthetase inhibitors;        -   (e) signal transduction inhibitors;        -   (f) cisplatin or platinum analogs;        -   (g) alkylating agents;        -   (h) anti-tubulin agents;        -   (i) antimetabolites;        -   (j) berberine;        -   (k) apigenin;        -   (l) amonafide;        -   (m) vinca alkaloids;        -   (n) 5-fluorouracil;        -   (o) curcumin;        -   (p) NF-κB inhibitors;        -   (q) rosmarinic acid;        -   (r) mitoguazone;        -   (s) tetrandrine;        -   (t) an inhibitor of mutant isocitrate dehydrogenase (IDH);        -   (u) a MGMT inhibitor; and        -   (v) an agent that inhibits NF-κB-enhanced expression of            MGMT.

In another alternative, the composition can comprise:

-   -   (i) dianhydrogalactitol; and    -   (ii) a therapeutic agent subject to chemosensitization selected        from the group consisting of:        -   (a) topoisomerase inhibitors;        -   (b) fraudulent nucleosides;        -   (c) fraudulent nucleotides;        -   (d) thymidylate synthetase inhibitors;        -   (e) signal transduction inhibitors;        -   (f) cisplatin or platinum analogs;        -   (g) alkylating agents;        -   (h) anti-tubulin agents;        -   (i) antimetabolites;        -   (j) berberine;        -   (k) apigenin;        -   (l) amonafide;        -   (m) vinca alkaloids;        -   (n) 5-fluorouracil;        -   (o) curcumin;        -   (p) NF-κB inhibitors;        -   (q) rosmarinic acid;        -   (r) mitoguazone; and        -   (s) tetrandrine;            wherein the dianhydrogalactitol acts as a chemosensitizer.

In yet another alternative, the composition can comprise:

-   -   (i) diacetyldianhydrogalactitol; and    -   (ii) a therapeutic agent subject to chemosensitization selected        from the group consisting of:        -   (a) topoisomerase inhibitors;        -   (b) fraudulent nucleosides;        -   (c) fraudulent nucleotides;        -   (d) thymidylate synthetase inhibitors;        -   (e) signal transduction inhibitors;        -   (f) cisplatin or platinum analogs;        -   (g) alkylating agents;        -   (h) anti-tubulin agents;        -   (i) antimetabolites;        -   (j) berberine;        -   (k) apigenin;        -   (l) amonafide;        -   (m) vinca alkaloids;        -   (n) 5-fluorouracil;        -   (o) curcumin;        -   (p) NF-κB inhibitors;        -   (q) rosmarinic acid;        -   (r) mitoguazone; and        -   (s) tetrandrine;            wherein the diacetyldianhydrogalactitol acts as a            chemosensitizer.

In yet another alternative, the composition comprises:

-   -   (i) dianhydrogalactitol; and    -   (ii) a therapeutic agent subject to chemopotentiation selected        from the group consisting of:        -   (a) topoisomerase inhibitors;        -   (b) fraudulent nucleosides;        -   (c) fraudulent nucleotides;        -   (d) thymidylate synthetase inhibitors;        -   (e) signal transduction inhibitors;        -   (f) cisplatin or platinum analogs;        -   (g) alkylating agents;        -   (h) anti-tubulin agents;        -   (i) antimetabolites;        -   (j) berberine;        -   (k) apigenin;        -   (l) amonafide;        -   (m) vinca alkaloids;        -   (n) 5-fluorouracil;        -   (o) curcumin;        -   (p) NF-κB inhibitors;        -   (q) rosmarinic acid;        -   (r) mitoguazone;        -   (s) tetrandrine; and        -   (t) biotherapeutics;            wherein the dianhydrogalactitol acts as a chemopotentiator.

In yet another alternative, the composition comprises:

-   -   (i) diacetyldianhydrogalactitol; and    -   (ii) a therapeutic agent subject to chemopotentiation selected        from the group consisting of:        -   (a) topoisomerase inhibitors;        -   (b) fraudulent nucleosides;        -   (c) fraudulent nucleotides;        -   (d) thymidylate synthetase inhibitors;        -   (e) signal transduction inhibitors;        -   (f) cisplatin or platinum analogs;        -   (g) alkylating agents;        -   (h) anti-tubulin agents;        -   (i) antimetabolites;        -   (j) berberine;        -   (k) apigenin;        -   (l) amonafide;        -   (m) vinca alkaloids;        -   (n) 5-fluorouracil;        -   (o) curcumin;        -   (p) NF-κB inhibitors;        -   (q) rosmarinic acid;        -   (r) mitoguazone;        -   (s) tetrandrine; and        -   (t) biotherapeutics;            wherein the diacetyldianhydrogalactitol acts as a            chemopotentiator.

In yet another alternative of a composition according to the presentinvention, the therapeutic agent is dianhydrogalactitol ordiacetyldianhydrogalactitol and the dianhydrogalactitol ordiacetyldianhydrogalactitol is subjected to a bulk drug productimprovement, wherein the bulk drug product improvement is selected fromthe group consisting of:

-   -   (a) salt formation;    -   (b) preparation as a homogeneous crystal structure;    -   (c) preparation as a pure isomer;    -   (d) increased purity;    -   (e) preparation with lower residual solvent content; and    -   (f) preparation with lower residual heavy metal content.

In still another alternative of a composition according to the presentinvention, the therapeutic agent is dianhydrogalactitol ordiacetyldianhydrogalactitol and the composition comprises a diluent,wherein the diluent is selected from the group consisting of:

-   -   (a) an emulsion;    -   (b) dimethylsulfoxide (DMSO);    -   (c) N-methylformamide (NMF)    -   (d) DMF;    -   (e) ethanol;    -   (f) benzyl alcohol;    -   (g) dextrose-containing water for injection;    -   (h) Cremophor;    -   (i) cyclodextrin; and    -   (j) PEG.

In still another alternative of a composition according to the presentinvention, the therapeutic agent is dianhydrogalactitol ordiacetyldianhydrogalactitol and the composition comprises a solventsystem, wherein the solvent system is selected from the group consistingof:

-   -   (a) an emulsion;    -   (b) dimethylsulfoxide (DMSO);    -   (c) N-methylformamide (NMF);    -   (d) DMF;    -   (e) ethanol;    -   (f) benzyl alcohol;    -   (g) dextrose-containing water for injection;    -   (h) Cremophor;    -   (i) cyclodextrin; and    -   (j) PEG.

In still another alternative of a composition according to the presentinvention, the therapeutic agent is dianhydrogalactitol ordiacetyldianhydrogalactitol and the composition comprises an excipient,wherein the excipient is selected from the group consisting of:

-   -   (a) mannitol;    -   (b) albumin;    -   (c) EDTA;    -   (d) sodium bisulfite;    -   (e) benzyl alcohol;    -   (f) a carbonate buffer; and    -   (g) a phosphate buffer.

In still another alternative of a composition according to the presentinvention, the therapeutic agent is dianhydrogalactitol ordiacetyldianhydrogalactitol and the dianhydrogalactitol ordiacetyldianhydrogalactitol is incorporated into a dosage form selectedfrom the group consisting of:

-   -   (a) tablets;    -   (b) capsules;    -   (c) topical gels;    -   (d) topical creams;    -   (e) patches;    -   (f) suppositories; and    -   (g) lyophilized dosage fills.

In still another alternative of a composition according to the presentinvention, the therapeutic agent is dianhydrogalactitol ordiacetyldianhydrogalactitol and the dianhydrogalactitol ordiacetyldianhydrogalactitol is incorporated into a dosage kit andpackaging selected from the group consisting of amber vials to protectfrom light and stoppers with specialized coatings to improve shelf-lifestability.

In still another alternative of a composition according to the presentinvention, the therapeutic agent is dianhydrogalactitol ordiacetyldianhydrogalactitol and the composition comprises a drugdelivery system selected from the group consisting of:

-   -   (a) nanocrystals;    -   (b) bioerodible polymers;    -   (c) liposomes;    -   (d) slow release injectable gels; and    -   (e) microspheres.

In still another alternative of a composition according to the presentinvention, the therapeutic agent is dianhydrogalactitol ordiacetyldianhydrogalactitol and the dianhydrogalactitol ordiacetyldianhydrogalactitol is present in the composition in a drugconjugate form selected from the group consisting of:

-   -   (a) a polymer system;    -   (b) polylactides;    -   (c) polyglycolides;    -   (d) amino acids;    -   (e) peptides; and    -   (f) multivalent linkers.

In yet another alternative of a composition according to the presentinvention, the therapeutic agent is a modified dianhydrogalactitol or amodified diacetyldianhydrogalactitol and the modification is selectedfrom the group consisting of:

-   -   (a) alteration of side chains to increase or decrease        lipophilicity;    -   (b) addition of an additional chemical functionality to alter a        property selected from the group consisting of reactivity,        electron affinity, and binding capacity; and    -   (c) alteration of salt form.

In yet another alternative of a composition according to the presentinvention, the therapeutic agent is dianhydrogalactitol ordiacetyldianhydrogalactitol and the dianhydrogalactitol ordiacetyldianhydrogalactitol is in the form of a prodrug system, whereinthe prodrug system is selected from the group consisting of:

-   -   (a) the use of enzyme sensitive esters;    -   (b) the use of dimers;    -   (c) the use of Schiff bases;    -   (d) the use of pyridoxal complexes; and    -   (e) the use of caffeine complexes.

In still another alternative of a composition according to the presentinvention, the therapeutic agent is dianhydrogalactitol ordiacetyldianhydrogalactitol and the composition further comprises atleast one additional therapeutic agent to form a multiple drug system,wherein the at least one additional therapeutic agent is selected fromthe group consisting of:

-   -   (a) an inhibitor of multi-drug resistance;    -   (b) a specific drug resistance inhibitor;    -   (c) a specific inhibitor of a selective enzyme;    -   (d) a signal transduction inhibitor;    -   (e) an inhibitor of a repair enzyme; and    -   (f) a topoisomerase inhibitor with non-overlapping side effects.

Analogous methods of use, compositions, and improvements also apply toother suboptimally administered therapeutic agents including, but notlimited to, Avastin (bevacizumab), Rituxan (rituximab), Nexavar(sorafenib), dasatinib, nilotinib, Provenge (sipuleucel-T), Tarceva(erlotinib), and Iressa (gefitinib).

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel compositions and methods to improve theutility of chemical agents including substituted hexitols such asdianhydrogalactitol or diacetyldianhydrogalactitol with suboptimalperformance for patients with cancer, as well as additional therapeuticagents or agents capable of therapeutic application including, but notlimited to, Avastin (bevacizumab), Rituxan (rituximab), Nexavar(sorafenib), dasatinib, nilotinib, Provenge (sipuleucel-T), Tarceva(erlotinib), Iressa (gefitinib), curcumin, berberine, and tetrandrine.The invention describes the novel development of improved pharmaceuticalingredients, dosage forms, excipients, solvents, diluents, drug deliverysystems, preservatives, more accurate drug administrations, improveddose determination and schedules, toxicity monitoring andameliorization, techniques or agents to circumvent or reduce toxicity,techniques and tools to identify/predict those patients who might have abetter outcome with a therapeutic agent by the use of phenotype orgenotype determination through the use of diagnostic kits orpharmacokinetic or metabolism monitoring approaches, the use of drugdelivery systems, novel prodrugs, polymer conjugates, novel routes ofadministration, other agents to potentiate the activity of the compoundsor inhibit the repair of suboptimal cellular effects or sub-lethaldamage or to “push” the cell into more destructive cellular phases suchas apoptosis. In some cases, the inventive examples include the use ofthese sub-optimal therapeutics in conjunction with radiation or otherconventional chemotherapeutic agents or biotherapeutic agents such asantibodies, vaccines, cytokines, lymphokines, gene and antisensetherapies, or other chemotherapeutic or biotherapeutic agents.

By definition, the term “suboptimal therapy” includes agents where PhaseI toxicity precluded further human clinical evaluation. It also includesthose agents from Phase II trials where limited or no significant tumorresponses were identified. In addition, it also includes those agents,the subject of Phase III clinical trials, whose outcome was eithermedically or statistically not significant to warrant submission orapproval by regulatory agencies for commercialization or commercializedagents whose response rates as a monotherapy are less than 25% or whoseside-effects are severe enough to limit wider utility. Agents withsuboptimal activity include but are not limited to the following:dianhydrogalactitol, diacetyldianhydrogalactitol, Avastin (bevacizumab),Rituxan (rituximab), Nexavar (sorafenib), dasatinib, nilotinib, Provenge(sipuleucel-T), Tarceva (erlotinib), and Iressa (gefitinib). Morespecifically, the inventive methods and compositions also focus onimprovements for substituted hexitols including dianhydrogalactitol anddiacetyldianhydrogalactitol.

(I) Suboptimal Therapeutics

In general, examples of compounds with suboptimal therapeutic activityinclude, but are not limited to, compounds of the following classes:DNA/nucleic acid binding/reactive agents, topoisomerase inhibitors,anti-tubulin agents, signal transduction inhibitors, protein synthesisinhibitors, inhibitors of DNA transcribing enzymes, DNA/RNAintercalating agents, DNA minor groove binders, drugs that block steroidhormone action, photochemically active agents, immune modifying agents,hypoxia selective cytotoxins, chemical radiation sensitizers andprotectors, antisense nucleic acids, oligonucleotides andpolynucleotides therapeutic agents, immune modifying agents, antitumorantibiotics, biotherapeutics, biologic agents such as cancer vaccines,antibody therapies, cytokines, lyphokines, gene therapies, nucleic acidtherapies, and cellular therapies. In some cases, a compound may fallwithin more than one of these classes; such compounds are also withinthe scope of the invention.

In some cases, compounds or compositions may be in current clinical usefor one or more indications, but yet be considered suboptimal foranother indication, such as a different type of malignancy, either interms of the cell type involved in the malignancy or in terms of thestage of the malignancy. Such compounds or compositions are within thescope of the invention.

Specific examples include: fluoropyrimidines; thiopurines; inhibitors ofnucleoside diphosphate reductase; 2′-deoxyribonucleoside analogs;nucleosides; folic acid analogs; methotrexate; 6-diazo-5-oxo-norleucine;L-asparaginase; N-(phosphoacetyl)-L-aspartic acid; nitrogen mustard;mechlorethamine; chlorambucil; melphalan; cyclophosphamide;estramustine; platinum complexes; nitrosoureas; BCNU; BCNU wafer(Gliadel); CCNU; streptozotocin; alkyl sulfonates; busulfan; clomesone;triazenylimidazoles and related triazenes; mitozolomide; temozolomide(Temodar); aziridines; tris(1-aziridinyl)phosphine sulfide;aziridinylphosphines;3,6-diaziridinyl-2,5-bis(carboethoxyamino)-1,4-benzoquinone (Diaziquone)(AZQ); AZQ analogs; bendamustine (Treanada); procarbazine;hexamethylamine; topoisomerase I inhibitors, including camptothecin andcamptothecin analogs; topoisomerase II inhibitors, includinganthracyclines, doxorubicin, epirubicin, etoposide; DNA intercalatingagents; amsacrine; CI-921((9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino]-N,5-dimethyl-4-acridinecarboxamide2-hydroxyethanesulfonate (1;1)), 1′-carbamate analogs of amsacrine;9-aminoacridine-4-carboxamides; acridine carboxamide; tricycliccarboxamides; 1-nitroacridine; acridine derivatives; diacridines;triacridines; podophyllotoxins; ellipticine; merbarone;benzisoquinolinediones; etoposide; teniposide; aminoanthraquinones;inhibitors of DNA-transcribing enzymes; transcription inhibitors;replication inhibitors; RNA replication inhibitors; DNA or RNApolymerase inhibitors; rifamycins; actinomycins; DNA minor groovebinding compounds; bisbenzimide (Hoechst 33258); mitomycins; CC-1065;mithramycins; chloromycins; olivomycins; phthalanilides; anthramycins;antimitotic agents; vinca alkaloids, including vinblastine and analogsand vincristine and analogs; navelbine; colchicine and analogs;bleomycin and analogs; estramustine; aromatase inhibitors; tamoxifen;LHRH antagonists and analogs porfimer; hematoporphyrins,electron-affinic oxygen mimetics; nitroaromatics; nitroheterocyclics;nitroimidazoles; tirapazamine, mitomycins; menadione and analogs;naphthoquinones; aziridoquinones; amine oxides; N-oxides; metalcomplexes; bioreductive agents; bioreductive alkylating agents;radiation sensitizers; radiation protectors; antisense agents; antigeneagents; transcription factor inhibitors; ODN complexes; ribozymes;double-stranded RNA; antitumor antibiotics; acivicin; aclararubicin;acodazole; acronycine; adozelesin; alanosine; allopurinol; altretamine;aminoglutethimide; amonafide; amsacrine; androgens; anguidine;aphidicolin glycinate; asaley; 5-azacytidine; 5-aza-2′-deoxycytidine;azathioprine; Baker's Antifol; β-2′-deoxythioguanosine; bisantrene HCl;bleomycin sulfate; busulfan; buthionine sulfoximine (BSO); BWA 773U82;BW 502U83 HCl; BW 7U85 mesylate; caracemide; carbetimer; carboplatin;carmustine; chlorambucil; chloroquinoxaline sulfonamide; chlorozotocin;chromomycin A3; cisplatin; cladribine; carboplatin; oxaliplatin;rhodamine compounds; corticosteroids; irinotecan (CPT-11); cristanol;cyclocytidine; cyclophosphamide; cytarabine; cytembena; dabis maleate;dacarbazine; dactinomycin; daunorubicin HCl; deazauridine; dexrazoxane;diacetyldianhydrogalactitol (DADAG), dianhydrogalactitol (DAG); didemninB; diethyldithiocarbamate; diglycoaldehyde; dihydro-5-azacytidine;doxorubicin; echinomycin; edatrexate; edelfosine; eflornithine;elsamitrucin; epirubicin; esorubicin; estramustine phosphate, estrogens;etanidazole; ethiofos; fadrazole; fazarabine; fenretinide; finasteride;flavone acetic acid; floxuridine; fludarabine phosphate; 5-fluorouracil;flutamide; gallium nitrate; gemcitabine; goserelin acetate; hepsulfam;hexamethylene bisacetamide; hydrazine sulfate; 4-hydroxyandrostenedione;hydroxyurea; idarubicin HCl; ifosfamide; 4-ipomeanol; iproplatin;isotretinoin; leuprolide acetate; levamisole; liposomal daunorubicin;liposomal doxorubicin; lomustine; lonidamine; maytansine; mechloethaminehydrochloride; menogaril; 6-mercaptopurine; mesna; N-methylformamide;mifepristone; mitoguazone; mitomycin C; mitotane; mitoxantronehydrochloride; nabilone; nafoxidine; neocarzinostatin; octreotideacetate; ormaplatin; oxaliplatin; paclitaxe; pala; pentostatin;piperazinedione; pipobroman; pirarubicin; piritrexim; piroxantronehydrochloride; plicamycin; porfimer sodium; predimustine; procarbazine;progestins; pyrazofurin; razoxane; sargramostim; semustine;spirogermanium; streptonigrin; streptozocin; sulofenur; suramin sodium;tamoxifen; taxotere; tegafur; teniposide; terephthalamidine; teroxirone;thioguanine; thiotepa; thymidine; tiazofurin; topotecan; tormifene;tretinoin; trifluoroperazine hydrochloride; trifluridine; trimetrexate;uracil mustard; vinblastine sulfate; vincristine sulfate; vindesine;vinorelbine; vinzolidine; Yoshi 864; zorubicin;2-chloro-2′deoxyadenosine; 3-deazauridine; 4-nitroestrone;6-methylmercaptopurine riboside; 9-aminocamptothecin; nitrocamptothecin;acodazole HCl; ADR-529; ICRF-187; amasacrine; aminothiadiazole; ADTA;amonafide; antibiotic FR901228; aphidicolin glycinate; AZT; bizelesin;brefeldins; wortmannins; cantharidins; bromodeoxyuridines; bryostatin;BSO; CAI; caracemide; chlorosulfaquinoxaline sulfonamide; cyclocytidineHCl; cyclodisone; cyclopentenylcytosine; deoxyspergualin; DHAC; didemninB; dideoxy-β-fluorouracil; dideoxyadenosine; dideoxyinosine;dihydrotriazine benzene sulfonyl fluoride; dolastatin 10; ecteinascidin743; etanidazole; ethiofos (WR-2721); fazarabine; flavopiridol;fludarabine phosphate; fostriecin; genistein; genistin;6″-O-malonylgenistin, 6″-O-acetylgenistin; daidzein; daidzin;6″-O-malonyldaidzin; 6″-O-acetylgenistin; glycitein; glycitin;6″-O-malonylglycitin; 6-O-acetylglycitin; hepsulfam; HMBA;iododeoxyuridine; ipomeanol; KNI-272; leucovorin calcium; levamisole;menogaril; merbarone; misonidazole; mitoguazone; mitoxantrone HCl;mitozolomide; O6-benzylguanine; PALA; pancratistatin; penclomedine;pentamethylmelamine HCl; pentamidine isethionate; pentostatin; perillylalcohol; phyllanthoside; pibenzimole HCl; piroxantrone; pyrazinediazohydroxide; pyrazoloacridine; quinocarmycins, rebeccamycins;rhizoxin; semustine; (methyl CCNU), suramin sodium; Nexavar; Gleevec;dasatinib (Sprycell); decitabine; 5-azacytidine (Vidaza);Homoharringtonine (HHT, omacetaxine); Taxol; temozolomide (Temodar);terephthalamidine; teroxirone; thioguanine; thymidine; tiazofurin; TMCA;topotecan; 5-fluorouracil; ras inhibitors; farnesylation inhibitors;bromodeoxyuridine, tetracycline compounds; arsenic trioxide;combretastatins; 2-methoxyestradiol; thalidomide and analogs;cephalotaxine derivatives; stributyrin; triciribine phosphate;trimetrexate; UCN-01; 7-hydroxystaurosporine; uridine; lycurium;ritrosulfan; artemisinin; artesunate; lonidamine; bromomannitol;pipobroman; phenesterin; pyrazine diazohydroxide; terephthalamidine;bufalin; FMDC; colchicine; thiocolchicine; colchicine analogs; LHRHanalogs; curcumin; berberine; tetrandrine; paclitaxel; MGBG; Nexavar(sorafenib); nilotinib; Provenge (sipuleucel-T); Tarceva (erlotinib);Iressa (gefitinib); and antibody therapies such as Avastin, Herceptin,Rituxan, and Erbitux.

In particular, the invention is directed to galactitols, substitutedgalactitols, and derivatives thereof, including dianhydrogalactitol anddiacetyldianhydrogalactitol.

The structure of dianhydrogalactitol is shown in Formula (I), below.

Also within the scope of the invention are derivatives ofdianhydrogalactitol that, for example, have the hydrogen of the hydroxylgroups replaced with lower alkyl, have the hydrogen attached to theepoxide ring replaced with lower alkyl, or have the methyl groupsattached to the same carbons that bear the hydroxyl groups replaced withlower alkyl or substituted with, for example, halo groups.

The structure of diacetyldianhydrogalactitol is shown in Formula (II),below.

Also within the scope of the invention are derivatives ofdiacetyldianhydrogalactitol that, for example, have the methyl groupsthat are part of the acetyl moieties replaced with lower alkyl, have thehydrogen attached to the epoxide ring replaced with lower alkyl, or havethe methyl groups attached to the same carbons that bear the acetylgroups replaced with lower alkyl or substituted with, for example, halogroups.

In another alternative, the invention is directed to an agent withsuboptimal activity selected from the group consisting of: Avastin(bevacizumab), Rituxan (rituximab), Nexavar (sorafenib), dasatinib,nilotinib, Provenge (sipuleucel-T), Tarceva (erlotinib), and Iressa(gefitinib).

Avastin (bevacizumab) is a humanized (from mouse) monoclonal antibodythat binds VEGF-A and is an angiogenesis inhibitor. It has been approvedor suggested for use in combination with standard chemotherapy formetastatic colon cancer and non-small-cell lung cancer. There have beensuggestions that it might be useful in metastatic breast cancer,although approval by the FDA for this specific indication was revoked.Bevacizumab has also been tried in macular degeneration, and clinicalstudies are also underway for bevacizumab in non-metastatic breastcancer, renal cell carcinoma, glioblastoma multiforme, ovarian cancer,hormone-refractory prostate cancer, non-metastatic unresectable livercancer, and metastatic or unresectable locally advanced pancreaticcancer.

Rituxan (rituximab) is a chimeric mouse/human monoclonal antibody thatbinds CD20, which is a marker primarily found on the surface of B cells.Rituximab is used in the treatment of many leukemias and lymphomas; itis also used to treat transplant rejection and autoimmune disorders. Itis being used in rheumatoid arthritis, particularly in combination withmethotrexate, and is being used to some extent in multiple sclerosis,systemic lupus erythematosus, autoimmune anemias such as autoimmunehemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenicpurpura, Evans syndrome, vasculitis such as Wegener's granulomatosis,pemphigus, pemphigoid, Type 1 diabetes mellitus, Sjögren's syndrome,Devic's disease, and thyroid-associated opththalmopathy.

Nexavar (sorafenib) has the chemical structure4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamideand is an inhibitor of several tyrosine protein kinases (VEGFR andPDGFR) and Raf. Sorafenib targets the MAP kinase pathway (Raf/Mek/Erkpathway). It is used or suggested for use in advanced renal cancer,hepatocellular carcinoma, non-responsive thyroid cancer, and recurrentglioblastoma.

Dasatinib is an oral multi-BRC/ABL and Src family tyrosine kinaseinhibitor that has the chemical structureN-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamidemonohydrate. It is currently used to treat chronic myelogenous leukemiaand Philadelphia-chromosome-positive acute lymphoblastic leukemia, andis being evaluated for treatment of numerous other cancers.

Nilotinib is a tyrosine kinase inhibitor that inhibits BCR-ABL, KIT,LCK, EPHA3, EPHA8, DDR1, DDR2, PDGFRB, MAPK11 and ZAK kinases and hasthe chemical structure4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamidehydrochloride salt. It is currently used to treat drug-resistant chronicmyelogenous leukemia.

Provenge (sipuleucel-T) is a therapeutic cancer vaccine that is aprotein subunit. It is currently being tried for metastatic,asymptomatic, hormone-refractory prostate cancer.

Tarceva (erlotinib) is an EGFR inhibitor that has the chemical structureN-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine and isused to treat non-small-cell lung cancer, pancreatic cancer, and othertypes of cancer.

Iressa (gefitinib) is also an EGFR inhibitor that has the chemicalstructureN-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine.Iressa also is effective in patients that have an EGFR mutation. Iressais considered particularly effective in treating some types ofnon-small-cell lung cancer, including adenocarcinoma.

(II) Dose Modification

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations to the time that the compound is administered, theuse of dose-modifying agents that control the rate of metabolism of thecompound, normal tissue protective agents, and other alterations.General examples include: variations of infusion schedules (e.g., bolusi.v. versus continuous infusion), the use of lymphokines (e.g., G-CSF,GM-CSF, EPO) to increase leukocyte count for improved immune response orfor preventing anemia caused by myelosuppressive agents, or the use ofrescue agents such as leucovorin for 5-FU or thiosulfate for cisplatintreatment. Specific inventive examples for substituted hexitols such asdianhydrogalactitol or diacetyldianhydrogalactitol include: continuousi.v. infusion for hours to days; biweekly administration; doses greaterthan 5 mg/m²/day; progressive escalation of dosing from 1 mg/m²/daybased on patient tolerance; doses less than 1 mg/m² for greater than 14days; use of caffeine to modulate metabolism; use of isoniazid tomodulate metabolism; selected and intermittent boost doseadministrations; bolus single and multiple doses escalating from 5mg/m²; or oral doses below 30 or above 130 mg/m².

(III) Route of Administration

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations in the route by which the compound is administered.General examples include: changing route from oral to intravenousadministration and vice versa; or the use of specialized routes such assubcutaneous, intramuscular, intraarterial, intraperitoneal,intralesional, intralymphatic, intratumoral, intrathecal,intravesicular, intracranial. Specific inventive examples forsubstituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: topical; intravesicular for bladdercancer; oral administration; slow release oral delivery; intrathecal;intraarterial; continuous infusion; or intermittent infusion.

(IV) Schedule of Administration

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations to the time that the compound is administered.General examples include: changing from a monthly administration to aweekly or daily dosing or variations of the schedule. Specific inventiveexamples for substituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: daily; weekly for three weeks,weekly for two weeks, biweekly; biweekly for three weeks with a 1-2 weekrest period; intermittent boost dose administration; or daily for oneweek then once per week for multiple weeks.

(V) Indications for Use

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations in the types of disease, clinical stage of diseasethat the compound is administered. General examples include: the use ofsolid tumor agents for leukemias and vice versa, the use of antitumoragents for the treatment of benign hyperproliferative disease such aspsoriasis or benign prostate hypertrophy. Specific inventive examplesfor substituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: use for the treatment of leukemias(acute and chronic, ALL CLL, CML CLL); myelodysplastic syndrome (MDS);angiogenic diseases; benign prostate hypertrophy; psoriasis; gout;autoimmune conditions; prevention of transplantation rejection;restenosis prevention in cardiovascular disease; mycosis fungoides; usein bone marrow transplantation; as an anti-infective agent; treatmentfor AIDS; or treatment for lymphoma.

(VI) Disease Stages

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations in the stage of disease at diagnosis/progressionthat the compound is administered. General examples include: the use ofchemotherapy for non-resectable local disease, prophylactic use toprevent metastatic spread or inhibit disease progression or conversionto more malignant stages. Specific inventive examples for substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitolinclude: use for the treatment of localized polyp stage colon cancer;leukoplakia in the oral cavity; angiogenesis inhibition to prevent orlimit metastatic spread; or against HIV with AZT, DDI, or reversetranscriptase inhibitors.

(VII) Other Indications

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by using the compound for non-malignant diseases and conditions.General examples include: premalignant conditions, benignhyperproliferative conditions, treatment of infections, parasites, usageto relieve pain, control of pleural effusions. Specific inventiveexamples for substituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: use as anti-infectives; use asantivirals; use as antibacterials; use for pleural effusions; use asantifungals; use as antiparasitics; use for eczema; use for shingles;use for condylomata; use as an anti-HPV agent; use as an anti-HSV agent.

(VIII) Patient Selection

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations to the type of patient that would best tolerate orbenefit from the use of the compound. General examples include: use ofpediatric doses for elderly patients, altered doses for obese patients;exploitation of co-morbid disease conditions such as diabetes,cirrhosis, or other conditions that may uniquely exploit a feature ofthe compound. Specific inventive examples for substituted hexitols suchas dianhydrogalactitol or diacetyldianhydrogalactitol include: patientswith disease conditions with high levels of metabolic enzymes, histonedeacetylase, protein kinases, or ornithine decarboxylase; patients withdisease conditions with low levels of metabolic enzymes, histonedeacetylase, protein kinases, or ornithine decarboxylase; patients withlow or high susceptibility to thrombocytopenia or neutropenia; patientsintolerant of GI toxicities; or over- or under-expression of jun, GPCR'sand signal transduction proteins, VEGF, prostate specific genes, proteinkinases, or telomerase.

(IX) Patient/Disease Phenotype

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by more precise identification of a patient's ability to tolerate,metabolize and exploit the use of the compound. General examplesinclude: use of diagnostic tools and kits to better characterize apatient's ability to process/metabolize a chemotherapeutic agent ortheir susceptibility to toxicity caused by potential specializedcellular, metabolic, organ system phenotypes: Specific inventiveexamples for substituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: diagnostic tools, techniques, kitsand assays to confirm a patient's particular phenotype and for themeasurement of metabolism enzymes and metabolites, histone deacetylase,protein kinases, ornithine decarboxylase, VEGF, prostate specific genes,protein kinases, telomerase, jun GPCR's, quantity or activity of MGMT,methylation of MGMT promoter, and mutant isocitrate dehydrogenase (IDH);or surrogate compound dosing or low dose drug pre-testing for enzymaticstatus.

(X) Patient/Disease Genotype

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by testing and analyzing a patient's genotype for unique featuresthat may be of value to predict efficacy, toxicity, metabolism, or otherfactors affecting the therapeutic efficacy of the drug. General examplesinclude: biopsy samples of tumors or normal tissues (e.g., white bloodcells) that may also be taken and analyzed to specifically tailor ormonitor the use of a particular drug against a gene target; studies ofunique tumor gene expression patterns; or analysis of SNP's (singlenucleotide polymorphisms), to enhance efficacy or to avoid particulardrug-sensitive normal tissue toxicities. Specific inventive examples forsubstituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: diagnostic tools, techniques, kitsand assays to confirm a patient's particular genotype; gene/proteinexpression chips and analysis; Single Nucleotide Polymorphisms (SNP's)assessment; SNP's for histone deacetylase, ornithine decarboxylase,GPCR's, protein kinases, telomerase, or jun; or identification and themeasurement of metabolism enzymes and metabolites.

(XI) Pre/Post-Treatment Preparation

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by specialized preparation of a patient prior to or after the useof a chemotherapeutic agent. General examples include: induction orinhibition of metabolizing enzymes, specific protection of sensitivenormal tissues or organ systems. Specific inventive examples forsubstituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: the use of colchicine or analogs;use of diuretics such as probenecid; use of uricase; non-oral use ofnicotinamide; sustained release forms of nicotinamide; use of inhibitorsof polyADP ribose polymerase; use of caffeine; use of leucovorin rescue;use of infection control; or use of antihypertensives.

(XII) Toxicity Management

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by use of additional drugs or procedures to prevent or reducepotential side-effects or toxicities. General examples include: the useof anti-emetics, anti-nausea, hematological support agents to limit orprevent neutropenia, anemia, thrombocytopenia, vitamins,antidepressants, treatments for sexual dysfunction, and other supportivetechniques. Specific inventive examples for substituted hexitols such asdianhydrogalactitol or diacetyldianhydrogalactitol include: the use ofcolchicine or analogs; use of diuretics such as probenecid; use ofuricase; non-oral use of nicotinamide; use of sustained release forms ofnicotinamide; use of inhibitors of poly ADP-ribose polymerase; use ofcaffeine; use of leucovorin rescue; use of sustained releaseallopurinol; non-oral use of allopurinol; use of bone marrow transplantstimulants, blood, platelet infusions, Neupogen, G-CSF, or GM-CSF; painmanagement; use of anti-inflammatories; fluids; corticosteroids; insulincontrol medications; anti-pyretics; anti-nausea treatments;anti-diarrhea treatment; N-acetyl cysteine; or antihistamines.

(XIII) Pharmacokinetic/Pharmacodynamic Monitoring

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by the use of monitoring drug levels after dosing in an effort tomaximize a patient's drug plasma level, to monitor the generation oftoxic metabolites, monitoring of ancillary medicines that could bebeneficial or harmful in terms of drug-drug interactions. Generalexamples include: the monitoring of drug plasma protein binding, andmonitoring of other pharmacokinetic or pharmacodynamic variables.Specific inventive examples for substituted hexitols such asdianhydrogalactitol or diacetyldianhydrogalactitol include: multipledeterminations of drug plasma levels; or multiple determinations ofmetabolites in the blood or urine.

(XIV) Drug Combinations

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by exploiting unique drug combinations that may provide a more thanadditive or synergistic improvement in efficacy or side-effectmanagement. General examples include: alkylating agents withanti-metabolites, topoisomerase inhibitors with antitubulin agents.Specific inventive examples for substituted hexitols such asdianhydrogalactitol or diacetyldianhydrogalactitol include: incombination with topoisomerase inhibitors; use in combination withfraudulent nucleosides; use in combination with fraudulent nucleotides;use in combination with thymidylate synthetase inhibitors; use incombination with signal transduction inhibitors; use in combination withcisplatin or platinum analogs; use in combination with alkylating agentssuch as the nitrosoureas (BCNU, Gliadel wafers, CCNU) bendamustine(Treanda); use in combination with anti-tubulin agents; use incombination with antimetabolites; use in combination with berberine; usein combination with apigenin; use in combination with amonafide; use incombination with colchicine and analogs; use in combination withgenistein; use in combination with etoposide; use in combination withcytarabine; use in combination with camptothecins; use in combinationwith vinca alkaloids; use in combination with topoisomerase inhibitors;use in combination with 5-fluorouracil; use in combination withcurcumin; use in combination with NF-κB inhibitors; use in combinationwith rosmarinic acid; use in combination with mitoguazone; use incombination with tetrandrine; use in combination with an inhibitor ofmutant isocitrate dehydrogenase (IDH); use in combination with a MGMTinhibitor; use in combination with an agent that inhibits NF-κB-enhancedexpression of MGMT; or use in combination with biological therapies suchas antibodies such as Avastin, Rituxan, Herceptin, Erbitux.

(XV) Chemosensitization

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by exploiting them as chemosensitizers where no measurable activityis observed when used alone but in combination with other therapeutics amore than additive or synergistic improvement in efficacy is observed.General examples include: misonidazole with alkylating agents, ortirapazamine with cisplatin. Specific inventive examples for substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitolinclude: as a chemosensitizer in combination with topoisomeraseinhibitors; as a chemosensitizer in combination with fraudulentnucleosides; as a chemosensitizer in combination with fraudulentnucleotides; as a chemosensitizer in combination with thymidylatesynthetase inhibitors; as a chemosensitizer in combination with signaltransduction inhibitors; as a chemosensitizer in combination withcisplatin or platinum analogs; as a chemosensitizer in combination withalkylating agents such as BCNU Gliadel wafers, CCNU, bendamustine(Treanda), temozolomide (Temodar); as a chemosensitizer in combinationwith anti-tubulin agents; as a chemosensitizer in combination withantimetabolites; as a chemosensitizer in combination with berberine; asa chemosensitizer in combination with apigenin; as a chemosensitizer incombination with amonafide; as a chemosensitizer in combination withcolchicine and analogs; as a chemosensitizer in combination withgenistein; as a chemosensitizer in combination with etoposide; as achemosensitizer in combination with cytarabine; as a chemosensitizer incombination with camptothecins; as a chemosensitizer in combination withvinca alkaloids; as a chemosensitizer in combination with topoisomeraseinhibitors; as a chemosensitizer in combination with 5-fluorouracil; asa chemosensitizer in combination with curcumin; as a chemosensitizer incombination with NF-κB inhibitors; as a chemosensitizer in combinationwith rosmarinic acid; as a chemosensitizer in combination withmitoguazone; or as a chemosensitizer in combination with tetrandrine.

(XVI) Chemopotentiation

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by exploiting them as chemopotentiators where minimal therapeuticactivity is observed alone but in combination with other therapeuticsunique drug a more than additive or synergistic improvement in efficacyis observed. General examples include: amonafide with cisplatin or 5-FU.Specific inventive examples for substituted hexitols such asdianhydrogalactitol or diacetyldianhydrogalactitol include: as achemopotentiator in combination with topoisomerase inhibitors; as achemopotentiator in combination with fraudulent nucleosides; as achemopotentiator in combination with thymidylate synthetase inhibitors;as a chemopotentiator in combination with signal transductioninhibitors; as a chemopotentiator in combination with cisplatin orplatinum analogs; as a chemopotentiator in combination with alkylatingagents such as BCNU, BCNU wafers, Gliadel, or bendamustine (Treanda); asa chemopotentiator in combination with anti-tubulin agents; as achemopotentiator in combination with antimetabolites; as achemopotentiator in combination with berberine; as a chemopotentiator incombination with apigenin; as a chemopotentiator in combination withamonafide; as a chemopotentiator in combination with colchicine andanalogs; as a chemopotentiator in combination with genistein; as achemopotentiator in combination with etoposide; as a chemopotentiator incombination with cytarabine; as a chemopotentiator in combination withcamptothecins; as a chemopotentiator in combination with vincaalkaloids; as a chemopotentiator in combination with topoisomeraseinhibitors; as a chemopotentiator in combination with 5-fluorouracil; asa chemopotentiator in combination with curcumin; as a chemopotentiatorin combination with NF-κB inhibitors; as a chemopotentiator incombination with rosmarinic acid; as a chemopotentiator in combinationwith mitoguazone; as a chemopotentiator in combination with ortetrandrine.

(XVII) Post-Treatment Patient Management

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by drugs, treatments and diagnostics to allow for the maximumbenefit to patients treated with a compound. General examples include:pain management, nutritional support, anti-emetics, anti-nauseatherapies, anti-anemia therapy, anti-inflammatories. Specific inventiveexamples for substituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: use with therapies associated withpain management; nutritional support; anti-emetics; anti-nauseatherapies; anti-anemia therapy; anti-inflammatories: antipyretics; orimmune stimulants.

(XVIII) Alternative Medicine/Therapeutic Support

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by the use of unapproved/non-conventional therapeutics or methodsto enhance effectiveness or reduce side effects. General examplesinclude: hypnosis, acupuncture, meditation, herbal medications andextracts, applied kinesiology, prayer. Specific inventive examples forsubstituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: hypnosis; acupuncture; meditation;herbal medications created either synthetically or through extractionincluding NF-κB inhibitors (such as parthenolide, curcumin, orrosmarinic acid); natural anti-inflammatories (including rhein orparthenolide); immunostimulants (such as those found in Echinacea);antimicrobials (such as berberine); flavonoids, isoflavones, andflavones (such as apigenenin, genistein, genistin, 6″-O-malonylgenistin,6″-O-acetylgenistin, daidzein, daidzin, 6″-O-malonyldaidzin,6″-O-acetylgenistin, glycitein, glycitin, 6″-O-malonylglycitin, and6-O-acetylglycitin); or applied kinesiology.

(XIX) Bulk Drug Product Improvements

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations in the pharmaceutical bulk substance. Generalexamples include: salt formation, homogeneous crystalline structure,pure isomers. Specific inventive examples for substituted hexitols suchas dianhydrogalactitol or diacetyldianhydrogalactitol include: saltformation; homogeneous crystalline structure; pure isomers; increasedpurity; or lower residual solvents and heavy metals.

(XX) Diluent Systems

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations in the diluents used to solubilize anddeliver/present the compound for administration. General examplesinclude: Cremophor-EL, cyclodextrins for poorly water soluble compounds.Specific inventive examples for substituted hexitols such asdianhydrogalactitol or diacetyldianhydrogalactitol include: use ofemulsions; dimethyl sulfoxide (DMSO); N-methylformamide (NMF);dimethylformamide (DMF); dimethylacetamide (DMA); ethanol; benzylalcohol; dextrose containing water for injection; Cremophor;cyclodextrins; or PEG.

(XXI) Solvent Systems

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations in the solvents used or required to solubilize acompound for administration or for further dilution. General examplesinclude: ethanol, dimethylacetamide (DMA). Specific inventive examplesfor substituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: the use of emulsions; DMSO; NMF;DMF; DMA; ethanol; benzyl alcohol; dextrose containing water forinjection; Cremophor; or PEG.

(XXII) Excipients

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations in the materials/excipients, buffering agents, orpreservatives required to stabilize and present a chemical compound forproper administration. General examples include: mannitol, albumin,EDTA, sodium bisulfite, benzyl alcohol. Specific inventive examples forsubstituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: the use of mannitol; albumin; EDTA;sodium bisulfite; benzyl alcohol; carbonate buffers; or phosphatebuffers.

(XXII) Dosage Forms

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations in the potential dosage forms of the compounddependent on the route of administration, duration of effect, plasmalevels required, exposure to side-effect normal tissues and metabolizingenzymes. General examples include: tablets, capsules, topical gels,creams, patches, suppositories. Specific inventive examples forsubstituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: the use of tablets; capsules;topical gels; topical creams; patches; suppositories; or lyophilizeddosage fills.

(XXIV) Dosage Kits and Packaging

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations in the dosage forms, container/closure systems,accuracy of mixing and dosage preparation and presentation. Generalexamples include: amber vials to protect from light, stoppers withspecialized coatings. Specific inventive examples for substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitolinclude: the use of amber vials to protect from light or stoppers withspecialized coatings to improve shelf-life stability.

(XXV) Drug Delivery Systems

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by the use of delivery systems to improve the potential attributesof a pharmaceutical product such as convenience, duration of effect,reduction of toxicities. General examples include: nanocrystals,bioerodible polymers, liposomes, slow release injectable gels,microspheres. Specific inventive examples for substituted hexitols suchas dianhydrogalactitol or diacetyldianhydrogalactitol include: the useof nanocrystals; bioerodible polymers; liposomes; slow releaseinjectable gels; or microspheres.

(XXVI) Drug Conjugate Forms

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations to the parent molecule with covalent, ionic, orhydrogen bonded moieties to alter the efficacy, toxicity,pharmacokinetics, metabolism, or route of administration. Generalexamples include: polymer systems such as polyethylene glycols,polylactides, polyglycolides, amino acids, peptides, or multivalentlinkers. Specific inventive examples for substituted hexitols such asdianhydrogalactitol or diacetyldianhydrogalactitol include: the use ofpolymer systems such as polyethylene glycols; polylactides;polyglycolides; amino acids; peptides; or multivalent linkers.

(XXVII) Compound Analogs

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations to the parent structure of a molecule withadditional chemical functionalities that may alter efficacy, or reducetoxicity, pharmacological performance, route of administration, oranother relevant factor for therapeutic efficacy. General examplesinclude: alteration of side chains to increase or decreaselipophilicity, additional chemical functionalities to alter reactivity,electron affinity, binding capacity, salt forms. Specific inventiveexamples for substituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: alteration of side chains toincrease or decrease lipophilicity; additional chemical functionalitiesto alter reactivity; electron affinity; binding capacity; or salt forms.

(XXVIII) Prodrugs

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by alterations to the molecule such that improved pharmaceuticalperformance is gained with a variant of the active molecule in thatafter introduction into the body a portion of the molecule is cleaved toreveal the preferred active molecule. General examples include: enzymesensitive esters, dimers, Schiff bases. Specific inventive examples forsubstituted hexitols such as dianhydrogalactitol ordiacetyldianhydrogalactitol include: the use of enzyme sensitive esters;dimers; Schiff bases; pyridoxal complexes; or caffeine complexes.

(XXIX) Multiple Drug Systems

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by the use of additional compounds, biological agents that whenadministered in the proper fashion, a unique and beneficial effect canbe realized. General examples include: inhibitors of multi-drugresistance, specific drug resistance inhibitors, specific inhibitors ofselective enzymes, signal transduction inhibitors, repair inhibition.Specific inventive examples for substituted hexitols such asdianhydrogalactitol or diacetyldianhydrogalactitol include: the use ofinhibitors of multi-drug resistance; specific drug resistanceinhibitors; specific inhibitors of selective enzymes; signaltransduction inhibitors; repair inhibition; or topoisomerase inhibitorswith non-overlapping side effects.

(XXX) Biotherapeutic Enhancement

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by their use in combination as sensitizers/potentiators withbiological response modifiers. General examples include: use incombination as sensitizers/poteniators with biological responsemodifiers, cytokines, lymphokines, therapeutic antibodies, antisensetherapies, gene therapies. Specific inventive examples for substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitolinclude: use in combination as sensitizers/potentiators with biologicalresponse modifiers; cytokines; lymphokines; therapeutic antibodies;antisense therapies; therapies such as Avastin, Herceptin, Rituxan, andErbitux; gene therapies; ribozymes; or RNA interference.

(XXXI) Biotherapeutic Resistance Modulation

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by exploiting their selective use to overcome developing orcomplete resistance to the efficient use of biotherapeutics. Generalexamples include: tumors resistant to the effects of biological responsemodifiers, cytokines, lymphokines, therapeutic antibodies, antisensetherapies, gene therapies. Specific inventive examples for substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitolinclude: the use against tumors resistant to the effects of biologicalresponse modifiers; cytokines; lymphokines; therapeutic antibodies;antisense therapies; therapies such as Avastin, Rituxan, Herceptin, andErbitux; gene therapies; ribozymes; or RNA interference.

(XXXII) Radiation Therapy Enhancement

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by exploiting their use in combination with ionizing radiation,phototherapies, heat therapies, or radio-frequency generated therapies.General examples include: hypoxic cell sensitizers, radiationsensitizers/protectors, photosensitizers, radiation repair inhibitors.Specific inventive examples for substituted hexitols such asdianhydrogalactitol or diacetyldianhydrogalactitol include: the use withhypoxic cell sensitizers; radiation sensitizers/protectors;photosensitizers; radiation repair inhibitors; thiol depletion;vaso-targeted agents; use with radioactive seeds, radionuclides,radiolabeled antibodies; or brachytherapy.

(XXXIII) Novel Mechanisms of Action

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by optimizing their utility by determining the various mechanismsof action, biological targets of a compound for greater understandingand precision to better exploit the utility of the molecule. Generalexamples include: Gleevec for chronic myelocytic leukemia (CML), arsenictrioxide for acute promyelocytic leukemia (APL), retinoic acid for APL.Specific inventive examples for substituted hexitols such asdianhydrogalactitol or diacetyldianhydrogalactitol include: the use withinhibitors of poly-ADP ribose polymerase; agents that effectvasculature; vasodilation; oncogenic targeted agents; signaltransduction inhibitors; EGFR inhibition; Protein Kinase C inhibition;Phospholipase C down-regulation; jun down-regulation; histone genes;VEGF; ornithine decarboxylase; jun D; v-jun; GPCRs; protein kinase A;telomerase, prostate specific genes; protein kinases; or histonedeacetylase.

(XXXIV) Selective Target Cell Population Therapeutics

Improvements for suboptimal chemotherapeutics including substitutedhexitols such as dianhydrogalactitol or diacetyldianhydrogalactitol aremade by more precise identification and exposure of the compound tothose select cell populations where the compound's effect can bemaximally exploited. General examples include: tirapazamine andmitomycin C for hypoxic cells, vinca alkaloids for cells enteringmitosis. Specific inventive examples for substituted hexitols such asdianhydrogalactitol or diacetyldianhydrogalactitol include: use againstradiation sensitive cells; radiation resistant cells; energy depletedcells; or endothelial cells.

Accordingly, one aspect of the present invention is a method to improvethe efficacy and/or reduce the side effects of suboptimally administereddrug therapy comprising the steps of:

(1) identifying at least one factor or parameter associated with theefficacy and/or occurrence of side effects of the drug therapy; and

(2) modifying the factor or parameter to improve the efficacy and/orreduce the side effects of the drug therapy.

Typically, the factor or parameter is selected from the group consistingof:

(1) dose modification;

(2) route of administration;

(3) schedule of administration;

(4) indications for use;

(5) selection of disease stage;

(6) other indications;

(7) patient selection;

(8) patient/disease phenotype;

(9) patient/disease genotype;

(10) pre/post-treatment preparation

(11) toxicity management;

(12) pharmacokinetic/pharmacodynamic monitoring;

(13) drug combinations;

(14) chemosensitization;

(15) chemopotentiation;

(16) post-treatment patient management;

(17) alternative medicine/therapeutic support;

(18) bulk drug product improvements;

(19) diluent systems;

(20) solvent systems;

(21) excipients;

(22) dosage forms;

(23) dosage kits and packaging;

(24) drug delivery systems;

(25) drug conjugate forms;

(26) compound analogs;

(27) prodrugs;

(28) multiple drug systems;

(29) biotherapeutic enhancement;

(30) biotherapeutic resistance modulation;

(31) radiation therapy enhancement;

(32) novel mechanisms of action; and

(33) selective target cell population therapeutics.

Typically, the hyperproliferative disease is cancer. Methods accordingto the present invention are applicable to many forms of cancer,including, but not limited to: (A) breast cancer, including: (1) ductalcarcinoma, including ductal carcinoma in situ (DCIS) (comedocarcinoma,cribriform, papillary, micropapillary), infiltrating ductal carcinoma(IDC), tubular carcinoma, mucinous (colloid) carcinoma, papillarycarcinoma, metaplastic carcinoma, and inflammatory carcinoma; (2)lobular carcinoma, including lobular carcinoma in situ (LCIS) andinvasive lobular carcinoma; and (3) Paget's disease of the nipple; (B)cancers of the female reproductive system, including: (1) cancers of thecervix uteri, including cervical intraepithelial neoplasia (Grade I),cervical intraepithelial neoplasia (Grade II), cervical intraepithelialneoplasia (Grade III) (squamous cell carcinoma in situ), keratinizingsquamous cell carcinoma, nonkeratinizing squamous cell carcinoma,verrucous carcinoma, adenocarcinoma in situ, adenocarcinoma in situ,endocervical type, endometrioid adenocarcinoma, clear celladenocarcinoma, adenosquamous carcinoma, adenoid cystic carcinoma, smallcell carcinoma, and undifferentiated carcinoma; (2) cancers of thecorpus uteri, including endometrioid carcinoma, adenocarcinoma,adenocanthoma (adenocarcinoma with squamous metaplasia), adenosquamouscarcinoma (mixed adenocarcinoma and squamous cell carcinoma, mucinousadenocarcinoma, serous adenocarcinoma, clear cell adenocarcinoma,squamous cell adenocarcinoma, and undifferentiated adenocarcinoma; (3)cancers of the ovary, including serous cystadenoma. serouscystadenocarcinoma, mucinous cystadenoma, mucinous cystadenocarcinoma,endometrioid tumor, endometrioid adenocarcinoma, clear cell tumor, clearcell cystadenocarcinoma, and unclassified tumor; (4) cancers of thevagina, including squamous cell carcinoma and adenocarcinoma; and (5)cancers of the vulva, including vulvar intraepithelial neoplasia (GradeI), vulvar intraepithelial neoplasia (Grade II), vulvar intraepithelialneoplasia (Grade III) (squamous cell carcinoma in situ); squamous cellcarcinoma, verrucous carcinoma, Paget's disease of the vulva,adenocarcinoma (NOS), basal cell carcinoma (NOS), and Bartholin's glandcarcinoma; (C) cancers of the male reproductive system, including: (1)cancers of the penis, including squamous cell carcinoma; (2) cancers ofthe prostate, including adenocarcinoma, sarcoma, and transitional cellcarcinoma of the prostate; (3) cancers of the testis, includingseminomatous tumor, nonseminomatous tumor, teratoma, embryonalcarcinoma, yolk sac tumor, and Choriocarcinoma; (D) cancers of thecardiac system, including sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; (E) cancers of the respiratory system, including squamous cellcarcinoma of the larynx, primary pleural mesothelioma, and squamous cellcarcinoma of the pharynx; (F) cancers of the lung, including squamouscell carcinoma (epidermoid carcinoma), variants of squamous cellcarcinoma, spindle cell carcinoma, small cell carcinoma, carcinoma ofother cells, carcinoma of intermediate cell type, combined oat cellcarcinoma, adenocarcinoma, acinar adenocarcinoma, papillaryadenocarcinoma, bronchiolo-alveolar carcinoma, solid carcinoma withmucus formation, large cell carcinoma, giant cell carcinoma, clear cellcarcinoma, and sarcoma; (G) cancers of the gastrointestinal tract,including: (1) cancers of the ampulla of Vater, including primaryadenocarcinoma, carcinoid tumor, and lymphoma; (2) cancers of the analcanal, including adenocarcinoma, squamous cell carcinoma, and melanoma;(3) cancers of the extrahepatic bile ducts, including carcinoma in situ,adenocarcinoma, papillary adenocarcinoma, adenocarcinoma, intestinaltype, mucinous adenocarcinoma, clear cell adenocarcinom, segnet-ringcell carcinoma, adenosquamous carcinoma, squamous cell carcinoma, smallcell (oat) carcinoma, undifferentiated carcinoma, carcinoma (NOS),sarcoma, and carcinoid tumor; (4) cancers of the colon and rectum,including adenocarcinoma in situ, adenocarcinoma, mucinousadenocarcinoma (colloid type; greater than 50% mucinous carcinoma),signet ring cell carcinoma (greater than 50% signet ring cell), squamouscell (epidermoid) carcinoma, adenosquamous carcinoma, small cell (oatcell) carcinoma, undifferentiated carcinoma, carcinoma (NOS), sarcoma,lymphoma, and carcinoid tumor; (5) cancers of the esophagus, includingsquamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma;(6) cancers of the gallbladder, including adenocarcinoma,adenocarcinoma, intestinal type, adenosquamous carcinoma, carcinoma insitu, carcinoma (NOS), clear cell adenocarcinoma, mucinousadenocarcinoma, papillary adenocarcinoma, signet-ring cell carcinoma,small cell (oat cell) carcinoma, squamous cell carcinoma, andundifferentiated carcinoma; (7) cancers of the lip and oral cavity,including squamous cell carcinoma; (8) cancers of the liver, includinghepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, and hemangioma; (9) cancers of theexocrine pancreas, including duct cell carcinoma, pleomorphic giant cellcarcinoma, giant cell carcinoma, osteoclastoid type, adenocarcinoma,adenosquamous carcinoma, mucinous (colloid) carcinoma,cystadenocarcinoma, acinar cell carcinoma, papillary carcinoma, smallcell (oat cell) carcinoma, mixed cell typed, carcinoma (NOS),undifferentiated carcinoma, endocrine cell tumors arising in the isletsof langerhans, and carcinoid; (10) cancers of the salivary glands,including acinic (acinar) cell carcinoma, adenoid cystic carcinoma(cylindroma), adenocarcinoma, squamous cell carcinoma, carcinoma inpleomorphic adenoma (malignant mixed tumor), mucoepidermoid carcinoma(well differentiated or low grade), and mucoepidermoid carcinoma (poorlydifferentiated or high grade); (11) cancers of the stomach, includingadenocarcinoma, papillary adenocarcinoma, tubular adenocarcinoma,mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamouscarcinoma, squamous cell carcinoma, small cell carcinoma,undifferentiated carcinoma, lymphoma, sarcoma, and carcinoid tumor; and(12) cancers of the small intestine, including adenocarcinoma, lymphoma,carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,neurofibroma, and fibroma; (H) cancers of the urinary system, including:(1) cancers of the kidney, including renal cell carcinoma, carcinoma ofBellini's collecting ducts, adenocarcinoma, papillary carcinoma, tubularcarcinoma, granular cell carcinoma, clear cell carcinoma(hypernephroma), sarcoma of the kidney, and nephroblastoma; (2) cancersof the renal pelvis and ureter, including transitional cell carcinoma,papillary transitional cell carcinoma, squamous cell carcinoma, andadenocarcinoma; (3) cancers of the urethra, including transitional cellcarcinoma, squamous cell carcinoma, and adenocarcinoma; and (4) cancersof the urinary bladder, including carcinoma in situ, transitionalurothelial cell carcinoma, papillary transitional cell carcinoma,squamous cell carcinoma, adenocarcinoma, undifferentiated; (I) cancersof muscle, bone, and soft tissue, including: (1) cancers of bone,including: (a) bone-forming: osteosarcoma; (b) cartilage-forming:chondrosarcoma and mesenchymal chondrosarcoma; (c) diant cell tumor,malignant; (d) Ewing's sarcoma; (e) vascular tumors:hemangioendothelioma, hemangiopericytoma, and angiosarcoma; (f)connective tissue tumors: fibrosarcoma, liposarcoma, malignantmesenchymoma, and undifferentiated sarcoma; and (g) other tumors:chordoma and adamantinoma of long bones; (2) cancers of soft tissues,including: alveolar soft-part sarcoma, angiosarcoma, epithelioidsarcoma, extraskeletal chondrosarcoma, fibrosarcoma, leiomyosarcoma,liposarcoma, malignant fibrous histiocytoma, malignanthemangiopericytoma, malignant mesenchymoma, malignant schwannoma,rhabdomyosarcoma, synovial sarcoma, and sarcoma (NOS); (3) cancers ofthe nervous system, including cancers of the skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), cancers of the meninges(meningioma, meningiosarcoma, gliomatosis), cancers of the brain(astrocytoma, medulloblastoma, glioma, ependymoma, germinoma(pilealoma), glioblastoma multiform, oligodendroglioma, schwannoma,retinoblastoma, congenital tumors), and cancers of the spinal cordneurofibroma, meningioma, glioma, sarcoma); (4) hematologic cancers,including myeloid leukemia (acute and chronic), acute lymphloblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma; myelodysplastic syndrome), Hodgkin's disease, andnon-Hodgkin's lymphoma (malignant lymphoma); (5) cancers of theendocrine system, including: (a) cancers of the thyroid gland, includingpapillary carcinoma (including those with follicular foci), follicularcarcinoma, medullary carcinoma, and undifferentiated (anaplastic)carcinoma; and (b) neuroblastomas, including sympathicoblastoma,sympathicogonioma, malignant ganglioneuroma, gangliosympathicoblastoma,and ganglioneuroma; (6) cancers of the skin, including squamous cellcarcinoma, spindle cell variant of squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma developing from sweat or sebaceous gland, andmalignant melanoma; (7) cancers of the eye, including: (a) cancers ofthe conjunctiva, including carcinoma of the conjunctiva; (b) cancers ofthe eyelid, including basal cell carcinoma, squamous cell carcinoma,melanoma of the eyelid, and sebaceous cell carcinoma; (c) cancers of thelacrimal gland, including adenocarcinoma, adenoid cystic carcinoma,carcinoma in pleomorphic adenoma, mucoepidermoid carcinoma, and squamouscell carcinoma; (d) cancers of the uvea, including spindle cellmelanoma, mixed cell melanoma, and epithelioid cell melanoma; (e)cancers of the orbit, including sarcoma of the orbit, soft tissue tumor,and sarcoma of bone; and (f) retinoblastoma. In particular, methodsaccording to the present invention and compositions suitable for useaccording to those methods are applicable to lower grade astrocytomasand other primary central nervous system tumors besides glioblastomamultiforme (GBM), as well as to central nervous system metastases ofother tumors including solid tumors and hematologic tumors (e.g.,breast, lung, bladder, and bowel tumors, leukemias, and lymphomas), inaddition to squamous cell non-small cell lung cancer. In addition,methods according to the present invention and compositions suitable foruse according to those methods are applicable to melanoma, breastlymphoma (both Hodgkins and non-Hodgkins), colorectal cancer, acutelymphoblastic leukemia, and for lowering the incidence of centralnervous system leukemia, non-small cell lung cancer, cervical carcinoma,bladder carcinoma, and metastatic hemangiopericytoma.

In one alternative, preferably, the substituted hexitol is selected fromthe group consisting of dianhydrogalactitol and a derivative thereof. Inthis alternative, more preferably, the substituted hexitol isdianhydrogalactitol. In another alternative, preferably, the substitutedhexitol is selected from the group consisting ofdiacetyldianhydrogalactitol and a derivative thereof. In thisalternative, more preferably, the substituted hexitol isdiacetyldianhydrogalactitol. Derivatives of dianhydrogalactitol and ofdiacetyldianhydrogalactitol are described above.

The following improvements all apply either to dianhydrogalactitol,diacetyldianhydrogalactitol, or derivatives of eitherdianhydrogalactitol or diacetyldianhydrogalactitol, as indicated withrespect to the specific improvement described below.

When the improvement is dose modification, the dose modification can be,but is not limited to, at least one dose modification selected from thegroup consisting of:

-   -   (a) continuous i.v. infusion for hours to days;    -   (b) biweekly administration;    -   (c) doses greater than 5 mg/m²/day;    -   (d) progressive escalation of dosing from 1 mg/m²/day based on        patient tolerance;    -   (e) use of caffeine to modulate metabolism;    -   (f) use of isonazid to modulate metabolism;    -   (g) selected and intermittent boosting of dosage administration;    -   (h) administration of single and multiple doses escalating from        5 mg/m²/day via bolus;    -   (i) oral dosages of below 30 mg/m²; and    -   (j) oral dosages of above 130 mg/m².

When the improvement is made by route of administration, the route ofadministration can be, but is not limited to, at least one route ofadministration selected from the group consisting of:

-   -   (a) topical administration;    -   (b) intravesicular administration for bladder cancer;    -   (c) oral administration;    -   (d) slow release oral delivery;    -   (e) intrathecal administration;    -   (f) intraarterial administration;    -   (g) continuous infusion; and    -   (h) intermittent infusion.

When the improvement is made by schedule of administration, the scheduleof administration can be, but is not limited to, at least one scheduleof administration selected from the group consisting of:

-   -   (a) daily administration;    -   (b) weekly administration;    -   (c) weekly administration for three weeks;    -   (d) biweekly administration;    -   (e) biweekly administration for three weeks with a 1-2 week rest        period;    -   (f) intermittent boost dose administration; and    -   (g) daily administration for one week for multiple weeks.

When the improvement is made by indication for use, the indication foruse can be, but is not limited to, at least one indication for useselected from the group consisting of:

-   -   (a) use for treatment of leukemias;    -   (b) use for treatment of myelodysplastic syndrome;    -   (c) use for treatment of angiogenic diseases;    -   (d) use for treatment of benign prostatic hyperplasia;    -   (e) use for treatment of psoriasis;    -   (f) use for treatment of gout;    -   (g) use for treatment of transplantation rejections;    -   (h) use for prevention of restenosis in cardiovascular disease;    -   (i) use for treatment of mycosis fungoides;    -   (j) use in bone marrow transplantation;    -   (k) use as an anti-infective agent;    -   (l) use for treatment of AIDS; and    -   (m) use for treatment of lymphoma.

When the improvement is made by selection of disease stage, theselection of disease stage can be, but is not limited to, at least oneselection of disease stage selected from the group consisting of:

-   -   (a) use for the treatment of localized polyp stage colon cancer;    -   (b) use for leukoplakia in the oral cavity;    -   (c) use for angiogenesis inhibition to prevent or limit        metastatic spread of a malignancy; and    -   (d) use for treatment of HIV with a therapy selected from the        group consisting of azidothymidine (AZT), dideoxyadenosine        (DDI), and reverse transcriptase inhibitors.

When the improvement is made by other indications, the other indicationscan be, but are not limited, to at least one other indication selectedfrom the group consisting of:

-   -   (a) use as an anti-infective agent;    -   (b) use as an antiviral agent;    -   (c) use as an antibacterial agent;    -   (d) use as an agent to treat pleural effusion;    -   (e) use as an antifungal agent;    -   (f) use as an anti-parasitic agent;    -   (g) use as an agent to treat eczema;    -   (h) use as an agent to treat herpes zoster (shingles);    -   (i) use as an agent to treat condylomata;    -   (j) use as an agent to treat human papilloma virus (HPV); and    -   (k) use as an agent to treat herpes simplex virus (HSV).

When the improvement is made by patient selection, the patient selectioncan be, but is not limited to, a patient selection carried out by acriterion selected from the group consisting of:

-   -   (a) selecting patients with a disease condition characterized by        a high level of a metabolic enzyme selected from the group        consisting of histone deacetylase and ornithine decarboxylase;    -   (b) selecting patients with a low or high susceptibility to a        condition selected from the group consisting of thrombocytopenia        and neutropenia;    -   (c) selecting patients intolerant of GI toxicities; and    -   (d) selecting patients characterized by over- or        under-expression of a gene selected from the group consisting of        c-Jun, a GPCR, a signal transduction protein, VEGF, a        prostate-specific gene, and a protein kinase.

The cellular proto-oncogene c-Jun encodes a protein that, in combinationwith c-Fos, forms the AP-1 early response transcription factor. Thisproto-oncogene plays a key role in transcription and interacts with alarge number of proteins affecting transcription and gene expression. Itis also involved in proliferation and apoptosis of cells that form partof a number of tissues, including cells of the endometrium and glandularepithelial cells. G-protein coupled receptors (GPCRs) are importantsignal transducing receptors. The superfamily of G protein coupledreceptors includes a large number of receptors. These receptors areintegral membrane proteins characterized by amino acid sequences thatcontain seven hydrophobic domains, predicted to represent thetransmembrane spanning regions of the proteins. They are found in a widerange of organisms and are involved in the transmission of signals tothe interior of cells as a result of their interaction withheterotrimeric G proteins. They respond to a diverse range of agentsincluding lipid analogues, amino acid derivatives, small molecules suchas epinephrine and dopamine, and various sensory stimuli. The propertiesof many known GPCR are summarized in S. Watson & S. Arkinstall, “TheG-Protein Linked Receptor Facts Book” (Academic Press, London, 1994),incorporated herein by this reference. GPCR receptors include, but arenot limited to, acetylcholine receptors, β-adrenergic receptors,β₃-adrenergic receptors, serotonin (5-hydroxytryptamine) receptors,dopamine receptors, adenosine receptors, angiotensin Type II receptors,bradykinin receptors, calcitonin receptors, calcitonin gene-relatedreceptors, cannabinoid receptors, cholecystokinin receptors, chemokinereceptors, cytokine receptors, gastrin receptors, endothelin receptors,γ-aminobutyric acid (GABA) receptors, galanin receptors, glucagonreceptors, glutamate receptors, luteinizing hormone receptors,choriogonadotrophin receptors, follicle-stimulating hormone receptors,thyroid-stimulating hormone receptors, gonadotrophin-releasing hormonereceptors, leukotriene receptors, Neuropeptide Y receptors, opioidreceptors, parathyroid hormone receptors, platelet activating factorreceptors, prostanoid (prostaglandin) receptors, somatostatin receptors,thyrotropin-releasing hormone receptors, vasopressin and oxytocinreceptors.

When the improvement is made by analysis of patient or diseasephenotype, the analysis of patient or disease phenotype can be, but isnot limited to, a method of analysis of patient or disease phenotypecarried out by a method selected from the group consisting of:

-   -   (a) use of a diagnostic tool, a diagnostic technique, a        diagnostic kit, or a diagnostic assay to confirm a patient's        particular phenotype;    -   (b) use of a method for measurement of a marker selected from        the group consisting of histone deacetylase, ornithine        decarboxylase, VEGF, a protein that is a gene product of a        prostate specific gene, a protein that is a gene product of jun,        a protein kinase, quantity or activity of MGMT, methylation of        MGMT promoter, and mutant isocitrate dehydrogenase (IDH);    -   (c) surrogate compound dosing; and    -   (d) low dose pre-testing for enzymatic status.

The role of O⁶-methylguanine DNA methyltransferase (MGMT) in humancancer has been described in M. Esteller & J. G. Herman, “GeneratingMutations but Providing Chemosensitivity: The Role of O⁶-MethylguanineDNA Methyltransferase in Human Cancer,” Oncology 23: 1-8 (2004),incorporated herein by this reference. MGMT is a DNA repair protein thatremoves mutagenic and cytotoxic adducts from O⁶-guanine in DNA.Alkylation of DNA at the O⁶ position of guanine is an important step inthe formation of mutations associated with malignancies, primarily dueto the tendency of the O⁶-methylguanine to pair with thymine duringreplication, resulting in the conversion of guanine-cytosine toadenine-thymine pairs (i.e., transversion mutations) in DNA.Furthermore, the O⁶-alkylguanine-DNA adduct (especially theO⁶-chloroethylguanine) may crosslink with the opposite cytosineresidues, blocking DNA replication, which requires separation of the twonucleotide strands of the double helix. MGMT protects cells againstthese lesions, transferring the alkyl group from the O⁶-guanine in DNAto an active cysteine within its own sequence in a reaction thatinactivates one MGMT molecule for each lesion repaired. The alkylatedMGMT protein then becomes detached from DNA and is targeted fordegradation by ubiquitination, which marks the ubiquitinated protein fordegradation. Accordingly, the ability of a cell to withstand such damageis directly related to the number of MGMT molecules that it contains andto the rate of de novo synthesis of MGMT in the cell.

Although MGMT can act at different rates on a wide variety of O⁶-alkylgroups (and even in a minor degree on O⁴-methylthymine which is analkylation product of the pyrimidine thymine), the majority of studieshave focused on the endogenous substrate O⁶-methylguanine. Of the morethan 12 different types of nitrogen and oxygen adducts of purine andpyrimidine bases produced by alkylating agents, O⁶-methylguanine is, infact, one of the least abundant, but of great importance in cancerbiology. O⁶-methylguanine affects cytosine methylation, the binding oftranscription factors, recombinogenic capacity, and may inhibit DNAreplication or cleavage if located at a replication origin or at atopoisomerase I site.

Amounts of MGMT protein in cells vary according to cellular type. Inhealthy cells, the level and activity of MGMT are regulated by proteinphosphorylation status, binding of the E6 papillomavirus oncoprotein,and the action of the tumor suppressor p53, glucocorticoid hormone, andother transcription factors over its 5′-CpG island, which includes aclassical promoter without TATA and CAAT boxes and a 59 by enhancerelement located at the first exon-intron boundary. Mutations in the MGMTgene, including point mutations, have been described in association withesophageal cancer in Chinese patients (L. Wang et al., “Mutations ofO⁶-Methylguanine-DNA Methyltransferase Gene in Esophageal Cancer Tissuesfrom Northern China,” Int. J. Cancer 71: 719-723 (1997), incorporatedherein by this reference), but the significance of these mutations isnot established.

The MGMT protein is decreased in some tumors with respect to theirnormal tissue counterpart; a subset of tumor cell lines, termed Mer-,completely lack MGMT activity. However, in most cases, loss ofexpression is not commonly due to deletion, mutation or rearrangement ofthe MGMT gene or instability of mRNA transcribed from the MGMT gene, soit is believed that other causes for loss of MGMT activity are involvedin the majority of cases where it occurs. Methylation of cytosine in CpGdinucleotides is the main epigenetic modification of DNA in normalmammalian cells. The human MGMT gene possesses a CpG island in the 5′portion of the gene. Hypermethylation of normally unmethylated CpGislands in the promoter regions of many genes, including p16^(INK4a),p14^(ARF), VHL, BRCA1, hMLH1 and E-cadherin, correlates with loss oftranscription of the genes involved. Hypermethylation of the MGMT CpGisland as the cause of MGMT transcriptional silencing in cell linesdefective in O⁶-methylguanine repair has been demonstrated. As for othergenes inactivated by CpG island methylation, hypermethylation of thepromoter region is accompanied by histone hypoacetylation andmethylation, binding of specific methyl-binding proteins, and loss ofnormal nucleosome positioning. All of these alterations can result in a“closed” chromatin state that prevents gene transcription. It has alsobeen shown that in vitro treatment of cancer cells withdemethylation-inducing drugs restores MGMT expression.

Typically, in cancer, the loss of MGMT function is associated withhypermethylation of the promoter region in a wide spectrum of humantumors; these tumors include gliomas, lymphomas, colon, head and neckand non-small-cell lung carcinomas. This aberrant MGMT promotermethylation has been correlated with loss of MGMT protein, lack of mRNAexpression, and loss of enzymatic activity. The promoterhypermethylation is considered to be an early event in carcinogenesis.

The causes of mutations in oncogenes and tumor suppressor genes aremultifactorial. Exogenous and endogenous compounds are known to causedamage in DNA, including deletions, insertions and base substitutions,either transversions (change of purine to pyrimidine or vice versa) ortransitions, change or purine to another purine or pyrimidine to anotherpyrimidine. A number of well-known reactions have been shown to generatepoint mutations. These reactions include: deamination of cytosine and5-methylcytosine to uracil and thymine, respectively; depurination; DNApolymerase infidelity; and oxidative damage from endogenously producedfree radicals. Other sources for mutations include abnormalities in DNArepair or replication. Several mechanisms can be invoked to contributeto the infidelity of DNA synthesis, including imbalances indeoxynucleotide triphosphate pools, mutations in DNA polymerase-α andslippage of DNA polymerase at nucleotide repeats.

In particular, one mutator pathway has been defined in human cancer.Germline mutations in the two DNA mismatch repair (MMR) genes hMLH1 andhMSH2 are the genetic abnormalities responsible for the vast majority ofhereditary nonpolyposis colorectal carcinoma cases; in these cancers,the presence of deletions and insertions in microsatellite sequences isa common hallmark. However, in the nonfamilial cases, the presence ofmicrosatellite instability is attributable to methylation-associatedsilencing of hMLH1 as indicated by the extremely tight associationbetween both phenomena, the restoration of MMR activity usingdemethylating agents, and the early (premalignant) appearance of hMLH1hypermethylation. The resulting epigenetic silencing of hMLH1 then leadsto mutations in target genes such as BAX or TGFRβII.

Methylation-mediated silencing of MGMT causes another strong andimportant mutator pathway in human cancer; this mutator pathway isconsidered to be more prevalent than microsatellite instability. Thepersistence of O⁶-methylguanine adducts, resulting from alkylatingagents, may cause DNA polymerase to misread base pairing according tothe normal Watson-Crick scheme because of the altered hydrogen-bondingproperties of a base that contains an additional methyl or ethyl group.Thus, O⁶-methylguanine is read as an adenine and mispairs with thymine.Supporting these data, the most common mutations caused by alkylatingagents are G:C to A:T transitions exemplified in the frequent generationof G to A transitions in the oncogene K-ras when the carcinogenN-methylnitrosourea, a mutagen that forms O⁶-methylguanine adducts, isused in experimentally induced tumor systems. The mutagenic effect isavoided if functional MGMT activity is present, and MGMT expression hasbeen shown to protect mammalian cell lines from spontaneous G:C to A:Ttransitions in the aprt gene. MGMT inactivation is also stronglyassociated with K-ras mutations in human tumors. K-ras mutation is rarein human primary breast carcinomas, but occurs in approximately half ofcolorectal carcinomas. This mutation distribution strongly resembles thepattern of MGMT promoter hypermethylation described; while MGMT aberrantmethylation is not present in breast carcinomas where K-ras mutationsare extremely rare, it occurs in approximately 40% of cases ofcolorectal carcinomas associated with loss of MGMT expression, and isalso frequent in non-small-cell lung carcinoma. Mutations that could bereversed by the activity of MGMT are also frequently found in the p53gene; typically, these are again G:C to A:T transitions, and theiroccurrence is strongly associated with hypermethylation of the MGMTpromoter; these mutations have been found in colon cancer, gliomas, andnon-small-cell lung carcinomas.

However, a reduction in functional MGMT activity is also associated withincreased sensitivity to alkylating agents, a number of which result inthe generation of alkylation at the O⁶ position of guanine. Thus,hypermethylation of the MGMT promoter can be associated with enhancedsensitivity of tumors with such hypermethylation to alkylating agents.However, there is no associated enhanced sensitivity for cisplatin, butthere is for cyclophosphamide.

It is important to note that MGMT hypermethylation alone, withouttreatment with an alkylating agent, is not a good prognostic factor. Infact, it is a poor prognostic factor, probably due to the finding thatpatients with epigenetic silencing of MGMT accumulate more mutations ingenes such as p53 and K-ras. This is an example of the differencebetween predictive and prognostic markers. Prognostic markers suggest adifference in outcome that is independent of the treatment received,including the possibility of no treatment. Predictive markers, on theother hand, predict a response, and thereby often survival differences,related to a specific form of therapy. Thus, while both types of markerscan predict differences in survival, predictive markers potentiallyprovide information leading to treatment decisions. MGMT methylation isdefinitively a negative prognostic marker, but a positive predictivemarker. Therefore, an analysis of the existence or lack ofhypermethylation of the MGMT promoter can be used in determination ofchemotherapeutic strategies. It is also possible to promote sensitivityof tumors to alkylating agents by administration of the MGMT inhibitorO⁶-benzylguanine.

U.S. Pat. No. 9,050,280 to Vlassenbroeck et al., incorporated herein bythis reference, discloses a method of detecting the presence and/oramount of a methylated or unmethylated gene of interest in aDNA-containing sample that comprises the steps of: (i) contacting theDNA-containing sample with a reagent which selectively modifiesunmethylated cytosine residues in the DNA to produce detectable modifiedresidues but which does not modify methylated cytosine residues; (ii)amplifying at least a portion of the methylated or unmethylated gene ofinterest using at least one primer pair, at least one primer of which isdesigned to bind only to the sequence of methylated or unmethylated DNAfollowing treatment with the reagent, wherein at least one primer in theprimer pair produces a detectable fluorescence signal duringamplification which is detected in real-time; and (iii) quantifying theresults of the real-time detection against a standard curve for themethylated or unmethylated gene of interest to produce an output of genecopy number. Preferred reagents that selectively modify unmethylatedcytosine residues in the DNA to produce detectable modified residues butwhich do not modify methylated cytosine residues include bisulfites,such as sodium bisulfite. The method can employ fluorescence resonanceenergy transfer (FRET) for detection. This method can be used fordetermination of the methylation status of the MGMT promoter.

United States Patent Application Publication No. 2007/0264672 byDasmahapatra et al., incorporated herein by this reference, disclosesmethods for assaying MGMT activity, including an immunoassay method, amethod employing labeled O⁶-benzylguanine, and a fluorescencepolarization method.

Isocitrate dehydrogenase (IDH) is an enzyme that normally catalyzes theoxidative decarboxylation of isocitrate, producing α-ketoglutarate andCO₂. This is a two-step process, which involves oxidation of isocitrate(a secondary alcohol) to oxalosuccinate (a ketone), followed by thedecarboxylation of the carboxyl group β to the ketone, formingα-ketoglutarate. In humans, IDH exists in three isoforms: IDH3 catalyzesthe third step of the citric acid cycle while converting NAD⁺ to NADH inthe mitochondria. The isoforms IDH1 and IDH2 catalyze the same reactionoutside the context of the citric acid cycle and use NADP⁺ as a cofactorinstead of NAD⁺. They localize to the cytosol as well as themitochondrion and peroxisome. In the context of cancer therapy, thesignificant isoforms are IDH1 and IDH2, especially IDH1. Specificmutations in the isocitrate dehydrogenase gene IDH1 have been found inseveral brain tumors including astrocytoma, oligodendroglioma, andglioblastoma multiforme, with mutations found in nearly all cases ofsecondary glioblastomas, which develop from lower-grade gliomas, butrarely in primary high-grade glioblastoma multiforme (F. E. Bleeker etal., “Recent Advances in the Molecular Understanding of Glioblastoma,”J. Neurooncol. 108: 11-27 (2012), incorporated herein by thisreference). Patients whose tumor had an IDH1 mutation had longersurvival. Furthermore, mutations of IDH2 and IDH1 were found in up to20% of cytogenetically normal acute myeloid leukemia (AML) (P. S. Wardet al., “The Common Feature of Leukemia-Associated IDH1 and IDH2Mutations is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to2-Hydroxyglutarate,” Cancer Cell 17: 225-234 (2010), incorporated hereinby this reference). These mutations are known to produce(D)-2-hydroxyglutarate, an abnormal product, from α-ketoglutarate.(D)-2-hydroxyglutarate can then accumulate to very high concentrations,which inhibits the function of enzymes that are dependent onα-ketoglutarate. This leads to a hypermethylated state of DNA andhistones, which results in different gene expression that can activateoncogenes and inactivate tumor-suppressor genes. Ultimately, this maylead to the types of cancer described above (R. J. Molenaar et al., “TheDriver and Passenger Effects of Isocitrate Dehydrogenase 1 and 2Mutations in Oncogenesis and Survival Prolongation,” Biochim. Biophys.Acta 1846: 326-341 (2014), incorporated herein by this reference).

U.S. Pat. No. 8,883,438 to Cantley et al., incorporated herein by thisreference, discloses methods of diagnosing a subject having a cellproliferation-related disorder or suspected of having a cellproliferation-related disorder characterized by: (i) the presence,distribution, or level of an isocitrate dehydrogenase 1 enzyme having amutation at residue 97 wherein the glycine residue has been replacedwith an aspartic acid residue (IDH1-G97D), which has 2-hydroxyglutarate(2HG) neoactivity, wherein 2HG neoactivity is the ability to convertα-ketoglutarate to 2-hydroxyglutarate, or (ii) elevated levels of 2HGdue to the presence of IDH1-G97D mutant enzyme having 2HG neoactivity,wherein the method comprises analyzing the presence, distribution, orlevel of 2HG in a tissue, product, or bodily fluid of said subject by achromatographic method, wherein an increased presence, distribution, orlevel of 2HG indicates the presence of the cell proliferation-relateddisorder, thereby diagnosing the subject for the cellproliferation-related disorder. The chromatographic method can be LC-MSor GC-MS. Alternatively, a mutation can be an IDH2-137 mutation. Amethod for treating a malignancy characterized by a mutation in IDH caninclude administration of a cellular structural analog of an α-hydroxyneoactivity product of Formula (S-II):

wherein: (i) each R^(a) and R^(b) is independently hydrogen, a metalion, or a negative charge; (ii) R^(c) is a hydrogen bond donor oracceptor, and can be bound to the carbon chain by a single or doublebond, as indicated by the dashed line; and (iii) n is 0, 1, or 2.Alternatively, an inhibitor of the neoactivity can be administered.

U.S. Pat. No. 8,685,660 to Vogelstein et al., incorporated herein bythis reference, discloses clinically significant mutations in IDH1 andIDH2, including: R132H in IDH1, R132S in IDH1, R132C in IDH1, R132L inIDH1, R132G in IDH1, R172M in IDH2, R172K in IDH2, and R172G in IDH2.

When the improvement is made by analysis of patient or disease genotype,the analysis of patient or disease genotype can be, but is not limitedto, a method of analysis of patient or disease genotype carried out by amethod selected from the group consisting of:

-   -   (a) use of a diagnostic tool, a diagnostic technique, a        diagnostic kit, or a diagnostic assay to confirm a patient's        particular genotype;    -   (b) use of a gene chip;    -   (c) use of gene expression analysis;    -   (d) use of single nucleotide polymorphism (SNP) analysis; and    -   (e) measurement of the level of a metabolite or a metabolic        enzyme.

The use of gene chips is described in A. J. Lee & S. Ramaswamy, “DNAMicroarrays in Biological Discovery and Patient Care” in Essentials ofGenomic and Personalized Medicine (G. S. Ginsburg & H. F. Willard, eds.,Academic Press, Amsterdam, 2010), ch. 7, pp. 73-88, incorporated hereinby this reference.

When the method is the use of single nucleotide polymorphism (SNP)analysis, the SNP analysis can be carried out on a gene selected fromthe group consisting of histone deacetylase, ornithine decarboxylase,VEGF, a prostate specific gene, c-Jun, and a protein kinase. The use ofSNP analysis is described in S. Levy and Y.-H. Rogers, “DNA Sequencingfor the Detection of Human Genome Variation” in Essentials of Genomicand Personalized Medicine (G. S. Ginsburg & H. F. Willard, eds.,Academic Press, Amsterdam, 2010), ch. 3, pp. 27-37, incorporated hereinby this reference.

Still other genomic techniques such as copy number variation analysisand analysis of DNA methylation can be employed. Copy number variationanalysis is described in C. Lee et al., “Copy Number Variation and HumanHealth” in Essentials of Genomic and Personalized Medicine (G. S.Ginsburg & H. F. Willard, eds., Academic Press, Amsterdam, 2010), ch. 5,pp. 46-59, incorporated herein by this reference. DNA methylationanalysis is described in S. Cottrell et al., “DNA Methylation Analysis:Providing New Insight into Human Disease” in Essentials of Genomic andPersonalized Medicine (G. S. Ginsburg & H. F. Willard, eds., AcademicPress, Amsterdam, 2010), ch. 6, pp. 60-72, incorporated herein by thisreference.

When the improvement is made by pre/post-treatment preparation, thepre/post-treatment preparation can be, but is not limited to, a methodof pre/post treatment preparation selected from the group consisting of:

-   -   (a) the use of colchicine or an analog thereof;    -   (b) the use of a uricosuric;    -   (c) the use of uricase;    -   (d) the non-oral use of nicotinamide;    -   (e) the use of a sustained-release form of nicotinamide;    -   (f) the use of an inhibitor of poly-ADP ribose polymerase;    -   (g) the use of caffeine;    -   (h) the use of leucovorin rescue;    -   (i) infection control; and    -   (j) the use of an anti-hypertensive agent.

Uricosurics include, but are not limited to, probenecid, benzbromarone,and sulfinpyrazone. A particularly preferred uricosuric is probenecid.Uricosurics, including probenecid, may also have diuretic activity.

Poly-ADP ribose polymerase inhibitors are described in G. J. Southan &C. Szabó, “Poly(ADP-Ribose) Inhibitors,” Curr. Med. Chem. 10: 321-240(2003), incorporated herein by this reference, and include nicotinamide,3-aminobenzamide, substituted 3,4-dihydroisoquinolin-1(2H)-ones andisoquinolin-1(2H)-ones, benzimidazoles, indoles, phthalazin-1(2H)-ones,quinazolinones, isoindolinones, phenanthridinones, and other compounds.

Leucovorin rescue comprises administration of folinic acid (leucovorin)to patients in which methotrexate has been administered. Leucovorin is areduced form of folic acid that bypasses dihydrofolate reductase andrestores hematopoietic function. Leucovorin can be administered eitherintravenously or orally.

In one alternative, wherein the pre/post treatment is the use of auricosuric, the uricosuric is probenecid or an analog thereof.

When the improvement is made by toxicity management, the toxicitymanagement can be, but is not limited to, a method of toxicitymanagement selected from the group consisting of:

-   -   (a) the use of colchicine or an analog thereof;    -   (b) the use of a uricosuric;    -   (c) the use of uricase;    -   (d) the non-oral use of nicotinamide;    -   (e) the use of a sustained-release form of nicotinamide;    -   (f) the use of an inhibitor of poly-ADP ribose polymerase;    -   (g) the use of caffeine;    -   (h) the use of leucovorin rescue;    -   (i) the use of sustained-release allopurinol;    -   (j) the non-oral use of allopurinol;    -   (k) the use of bone marrow transplants;    -   (l) the use of a blood cell stimulant;    -   (m) the use of blood or platelet infusions;    -   (n) the administration of an agent selected from the group        consisting of filgrastim (Neupogen®), G-CSF, and GM-CSF;    -   (o) the application of a pain management technique;    -   (p) the administration of an anti-inflammatory agent;    -   (q) the administration of fluids;    -   (r) the administration of a corticosteroid;    -   (s) the administration of an insulin control medication;    -   (t) the administration of an antipyretic;    -   (u) the administration of an anti-nausea treatment;    -   (v) the administration of an anti-diarrheal treatment;    -   (w) the administration of N-acetylcysteine; and    -   (x) the administration of an antihistamine.

Filgrastim is a granulocytic colony-stimulating factor (G-CSF) analogproduced by recombinant DNA technology that is used to stimulate theproliferation and differentiation of granulocytes and is used to treatneutropenia; G-CSF can be used in a similar manner. GM-CSF isgranulocyte macrophage colony-stimulating factor and stimulates stemcells to produce granulocytes (eosinophils, neutrophils, and basophils)and monocytes; its administration is useful to prevent or treatinfection.

Anti-inflammatory agents are well known in the art and includecorticosteroids and non-steroidal anti-inflammatory agents (NSAIDs).Corticosteroids with anti-inflammatory activity include, but are notlimited to, hydrocortisone, cortisone, beclomethasone dipropionate,betamethasone, dexamethasone, prednisone, methylprednisolone,triamcinolone, fluocinolone acetonide, and fludrocortisone.Non-steroidal anti-inflammatory agents include, but are not limited to,acetylsalicylic acid (aspirin), sodium salicylate, choline magnesiumtrisalicylate, salsalate, diflunisal, sulfasalazine, olsalazine,acetaminophen, indomethacin, sulindac, tolmetin, diclofenac, ketorolac,ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofin, oxaprozin,mefenamic acid, meclofenamic acid, piroxicam, meloxicam, nabumetone,rofecoxib, celecoxib, etodolac, nimesulide, aceclofenac, alclofenac,alminoprofen, amfenac, ampiroxicam, apazone, araprofen, azapropazone,bendazac, benoxaprofen, benzydamine, bermoprofen, benzpiperylon,bromfenac, bucloxic acid, bumadizone, butibufen, carprofen, cimicoxib,cinmetacin, cinnoxicam, clidanac, clofezone, clonixin, clopirac,darbufelone, deracoxib, droxicam, eltenac, enfenamic acid, epirizole,esflurbiprofen, ethenzamide, etofenamate, etoricoxib, felbinac,fenbufen, fenclofenac, fenclozic acid, fenclozine, fendosal, fentiazac,feprazone, filenadol, flobufen, florifenine, flosulide, flubichinmethanesulfonate, flufenamic acid, flufenisal, flunixin, flunoxaprofen,fluprofen, fluproquazone, furofenac, ibufenac, imrecoxib, indoprofen,isofezolac, isoxepac, isoxicam, licofelone, lobuprofen, lomoxicam,lonazolac, loxaprofen, lumaricoxib, mabuprofen, miroprofen,mofebutazone, mofezolac, morazone, nepafanac, niflumic acid, nitrofenac,nitroflurbiprofen, nitronaproxen, orpanoxin, oxaceprol, oxindanac,oxpinac, oxyphenbutazone, pamicogrel, parcetasal, parecoxib, parsalmide,pelubiprofen, pemedolac, phenylbutazone, pirazolac, pirprofen,pranoprofen, salicin, salicylamide, salicylsalicylic acid, satigrel,sudoxicam, suprofen, talmetacin, talniflumate, tazofelone, tebufelone,tenidap, tenoxicam, tepoxalin, tiaprofenic acid, tiaramide, tilmacoxib,tinoridine, tiopinac, tioxaprofen, tolfenamic acid, triflusal, tropesin,ursolic acid, valdecoxib, ximoprofen, zaltoprofen, zidometacin, andzomepirac, and the salts, solvates, analogues, congeners, bioisosteres,hydrolysis products, metabolites, precursors, and prodrugs thereof.

The clinical use of corticosteroids is described in B. P. Schimmer & K.L. Parker, “Adrenocorticotropic Hormone; Adrenocortical Steroids andTheir Synthetic Analogs; Inhibitors of the Synthesis and Actions ofAdrenocortical Hormones” in Goodman & Gilman's The Pharmacological Basisof Therapeutics (L. L. Brunton, ed., 11^(th) ed., McGraw-Hill, New York,2006), ch. 59, pp. 1587-1612, incorporated herein by this reference.

Anti-nausea treatments include, but are not limited to, ondansetron,metoclopramide, promethazine, cyclizine, hyoscine, dronabinol,dimenhydrinate, diphenhydramine, hydroxyzine, medizine, dolasetron,granisetron, palonosetron, ramosetron, domperidone, haloperidol,chlorpromazine, fluphenazine, perphenazine, prochlorperazine,betamethasone, dexamethasone, lorazepam, and thiethylperazine.

Anti-diarrheal treatments include, but are not limited to,diphenoxylate, difenoxin, loperamide, codeine, racecadotril, octreoside,and berberine.

N-acetylcysteine is an antioxidant and mucolytic that also providesbiologically accessible sulfur.

When the improvement is made by pharmacokinetic/pharmacodynamicmonitoring, the pharmacokinetic/pharmacodynamic monitoring can be, butis not limited to a method selected from the group consisting of:

-   -   (a) multiple determinations of blood plasma levels; and    -   (b) multiple determinations of at least one metabolite in blood        or urine.

Typically, determination of blood plasma levels or determination of atleast one metabolite in blood or urine is carried out by immunoassays.Methods for performing immunoassays are well known in the art, andinclude radioimmunoassay, ELISA (enzyme-linked immunosorbent assay),competitive immunoassay, immunoassay employing lateral flow test strips,and other assay methods.

When the improvement is made by drug combination, the drug combinationcan be, but is not limited to, a drug combination selected from thegroup consisting of:

-   -   (a) use with topoisomerase inhibitors;    -   (b) use with fraudulent nucleosides;    -   (c) use with fraudulent nucleotides;    -   (d) use with thymidylate synthetase inhibitors;    -   (e) use with signal transduction inhibitors;    -   (f) use with cisplatin or platinum analogs;    -   (g) use with alkylating agents;    -   (h) use with anti-tubulin agents;    -   (i) use with antimetabolites;    -   (j) use with berberine;    -   (k) use with apigenin;    -   (l) use with amonafide;    -   (m) use with vinca alkaloids;    -   (n) use with 5-fluorouracil;    -   (o) use with curcumin;    -   (p) use with NF-κB inhibitors;    -   (q) use with rosmarinic acid;    -   (r) use with mitoguazone;    -   (s) use with tetrandrine;    -   (t) use with an inhibitor of mutant isocitrate dehydrogenase        (IDH);    -   (u) use with a MGMT inhibitor; and    -   (v) use with an agent that inhibits NF-κB-enhanced expression of        MGMT.

Topoisomerase inhibitors include, but are not limited to, irinotecan,topotecan, camptothecin, lamellarin D, amsacrine, etoposide, etoposidephosphate, teniposide, doxorubicin, and ICRF-193.

Fraudulent nucleosides include, but are not limited to, cytosinearabinoside, gemcitabine, and fludarabine; other fraudulent nucleosidesare known in the art.

Fraudulent nucleotides include, but are not limited to, tenofovirdisoproxil fumarate and adefovir dipivoxil; other fraudulent nucleotidesare known in the art.

Thymidylate synthetase inhibitors include, but are not limited to,raltitrexed, pemetrexed, nolatrexed, ZD9331, GS7094L, fluorouracil, andBGC 945.

Signal transduction inhibitors are described in A. V. Lee et al., “NewMechanisms of Signal Transduction Inhibitor Action: Receptor TyrosineKinase Down-Regulation and Blockade of Signal Transactivation,” Clin.Cancer Res. 9: 516s (2003), incorporated herein in its entirety by thisreference.

Alkylating agents include, but are not limited to, Shionogi 254-S,aldo-phosphamide analogues, altretamine, anaxirone, Boehringer MannheimBBR-2207, bendamustine, bestrabucil, budotitane, Wakunaga CA-102,carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil,cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233,cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)₂, diphenylspiromustine,diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R,ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium,fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide,iproplatin, lomustine, mafosfamide, melphalan, mitolactol, Nippon KayakuNK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU,prednimustine, Proter PTT-119, ranimustine, semustine, SmithKlineSK&F-101772, Yakult Honsha SN-22, spiromustine, Tanabe Seiyaku TA-077,tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol, asdescribed in U.S. Pat. No. 7,446,122 by Chao et al., incorporated hereinby this reference.

Anti-tubulin agents include, but are not limited to, vinca alkaloids,taxanes, podophyllotoxin, halichondrin B, and homohalichondrin B.

Antimetabolites include, but are not limited to: methotrexate,pemetrexed, 5-fluorouracil, capecitabine, cytarabine, gemcitabine,6-mercaptopurine, and pentostatin, alanosine, AG2037 (Pfizer),5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium,carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabinephosphate stearate, cytarabine conjugates, Lilly DATHF, Merrill-DowDDFC, deazaguanine, dideoxycytidine, dideoxyguanosine, didox, YoshitomiDMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, N-(2′-furanidyl)-5-fluorouracil,Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, LillyLY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine,NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567,Warner-Lambert PALA, piritrexim, plicamycin, Asahi Chemical PL-AC,Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate,tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, TaihoUFT and uricytin.

Berberine has antibiotic activity and prevents and suppresses theexpression of pro-inflammatory cytokines and E-selectin, as well asincreasing adiponectin expression.

Apigenin is a flavone that can reverse the adverse effects ofcyclosporine and has chemoprotective activity, either alone orderivatized with a sugar.

Amonafide is a topoisomerase inhibitor and DNA intercalator that hasanti-neoplastic activity.

Curcumin is believed to have anti-neoplastic, anti-inflammatory,antioxidant, anti-ischemic, anti-arthritic, and anti-amyloid propertiesand also has hepatoprotective activity.

NF-κB inhibitors include, but are not limited to, bortezomib.

Rosmarinic acid is a naturally-occurring phenolic antioxidant that alsohas anti-inflammatory activity.

Mitoguazone is an inhibitor of polyamine biosynthesis throughcompetitive inhibition of S-adenosylmethionine decarboxylase.

Tetrandrine has the chemical structure6,6′,7,12-tetramethoxy-2,2′-dimethyl-1 β-berbaman and is a calciumchannel blocker that has anti-inflammatory, immunologic, andantiallergenic effects, as well as an anti-arrhythmic effect similar tothat of quinidine. It has been isolated from Stephania tetranda andother Asian herbs.

In one alternative, when the drug combination is use with an alkylatingagent, the alkylating agent can be selected from the group consisting ofBCNU, BCNU wafers (Gliadel), and CCNU.

Inhibitors of mutant isocitrate dehydrogenase (IDH) are known in theart.

U.S. Pat. No. 8,957,068 to Caferro et al., incorporated herein by thisreference, discloses 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors ofmutant IDH, including compounds of Formula (S-I):

wherein:

-   -   (i) R¹ and R² are each independently hydrogen, deuterium, halo,        hydroxyl, NH₂, aryl, heteroaryl, or optionally substituted C₁-C₄        alkyl, wherein C₁-C₄ alkyl is optionally substituted with one to        three substituents each independently selected from the group        consisting of: halo, hydroxyl, and NH₂;    -   (ii) R^(3a) is hydrogen, deuterium, C₁-C₆ alkyl, phenyl, or        benzyl;    -   (iii) R^(3b) is hydrogen, deuterium, C₁-C₆ alkyl; or R^(3a) and        R^(3b) are joined together forming an optionally substituted 3-7        membered cycloalkyl ring or an optionally substituted 4-7        membered heterocyclic ring, wherein said cycloalkyl and        heterocyclic rings are each optionally substituted with one or        two substituents each independently selected from the group        consisting of: halo, hydroxyl, oxo, NH₂, and C₁-C₃ alkyl;    -   (iv) R^(4a) is hydrogen, C₁-C₆ alkyl, optionally substituted        phenyl, optionally substituted benzyl, optionally substituted        heteroaryl, or methylene-dibenzene, wherein said phenyl, benzyl,        and heteroaryl rings are optionally substituted with one to        three substituents each independently selected from the group        consisting of: halo, hydroxyl, cyano, nitro, C₁-C₄ alkoxy, C₁-C₃        haloalkyl, C₁-C₃ haloalkoxy, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,        phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic,        phenoxy, —COOR^(b), —SO₂R^(b), —NHC(O)R^(b), and —NR^(b)R^(b);    -   (v) R^(4b) is hydrogen, deuterium, or C₁-C₃ alkyl, or R^(4a) and        R^(4b) are joined together forming an optionally substituted 3-7        membered cycloalkyl ring or an optionally substituted 4-7        membered heterocyclic ring, wherein said cycloalkyl and        heterocyclic rings are optionally substituted with one or two        substituents each independently selected from the group        consisting of: halo, hydroxyl, oxo, NH₂, and C₁-C₃ alkyl,        provided that only one of R^(3a) and R^(3b) and R^(4a) and        R^(4b) are joined together forming a ring;    -   (vi) R^(5a) is hydrogen or deuterium;

(vii) R^(5b) is hydrogen, deuterium, methyl, ethyl, CD₃, CF₃, CH₂F, orCHF₂ and

-   -   (viii) R⁶ is optionally substituted C₁-C₆ alkyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted heterocyclyl, or optionally substituted C₃-C₁₀        cycloalkyl;    -   (viii) wherein said C₁-C₆ alkyl is optionally substituted with        one substituent selected from the group consisting of hydroxyl,        C₁-C₃ alkoxy and —OR^(a);    -   (ix) wherein said aryl, heteroaryl, heterocyclic and C₃-C₁₀        cycloalkyl are optionally substituted with one to three        substituents each independently selected from the group        consisting of: halo; hydroxyl; cyano; nitro; C₁-C₄ alkoxy; C₁-C₃        haloalkyl; C₁-C₃ haloalkoxy; C₁-C₆ alkyl; C₃-C₆ cycloalkyl        optionally substituted with one to three substituents each        independently selected from the group consisting of: hydroxyl,        cyano, C₁-C₃ alkyl, C₁-C₃ alkoxy, and C₁-C₃ haloalkyl; phenyl        optionally substituted with one to three substituents each        independently selected from the group consisting of: halo,        hydroxyl, cyano, nitro, C₁-C₃ alkoxy, C₁-C₃ haloalkyl, C₁-C₃        haloalkoxy, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, 5-6 membered        heteroaryl, 5-6 membered heterocyclic, phenoxy, —COOR^(b),        —SO₂R^(b), —NHC(O)R^(b), and —NR^(b)R^(b); 5-6 membered        heteroaryl optionally substituted with one to three substituents        each independently selected from the group consisting of: halo,        hydroxyl, cyano, C₁-C₃ alkyl, C₁-C₃ alkoxy; 5-6 membered        heterocyclyl optionally substituted with one to three        substituents each independently selected from the group        consisting of: halo, hydroxyl, oxo, NH₂, and C₁-C₃ alkyl;        —CH₂R^(a); —OR^(a); —C(O)R^(a); —NR^(a)R^(b); —COOR^(a);        —SO₂R^(a); —SO₂R^(b); NHC(O)R^(a); —NHC(O)R^(b);        —C(O)NR^(a)R^(b); —C(O)NHR^(b); and —SO²NR^(b)R^(b); or    -   (x) R^(5b) and R⁶ are joined together forming an optionally        substituted C₃-C₇ cycloalkyl group or an optionally substituted        group of Formula (S-I(a)):

wherein n is 1, 2, or 3; and

-   -   (xii) said C₃-C₇ cycloalkyl and group of formula (a) are        optionally substituted with one to three substituents each        independently selected from the group consisting of: halo,        hydroxyl, cyano, nitro, C₁-C₃ alkoxy, C₁-C₃ haloalkyl, C₁-C₃        haloalkoxy, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, 5-6 membered        heteroaryl, 5-6 membered heterocyclyl, benzyloxy, —COOR^(b),        —SO₂R^(b), —NHC(O)R^(b), and —NR^(b)R^(b);    -   (xiii) each R^(a) is independently optionally substituted        phenyl, optionally substituted heteroaryl, optionally        substituted heterocyclic, or optionally substituted C₃-C₇        cycloalkyl,    -   (xiv) wherein said phenyl and heteroaryl are optionally        substituted with one to three substituents each independently        selected from the group consisting of halo, hydroxyl, cyano,        nitro, C₁-C₃ alkoxy, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy, and        C₁-C₃ alkyl,    -   (xv) wherein said heterocyclic is optionally substituted with        one to three substituents each independently selected from the        group consisting of halo, hydroxyl, oxo, C₁-C₃ alkoxy, C₁-C₃        haloalkyl, C₁-C₃ haloalkoxy, C₁-C₄ alkyl, C₃-C₅ cycloalkyl,        —C(O)R^(b), and —NR^(b)R^(b); and    -   (xvi) wherein said C₃-C₇ cycloalkyl is optionally substituted        with one to three substituents each independently selected from        the group consisting of halo, hydroxyl, oxo, C₁-C₃ alkoxy, C₁-C₃        haloalkyl, C₁-C₃ haloalkoxy, and C₁-C₃ alkyl; and    -   (xvii) each R^(b) is independently hydrogen or C₁-C₆ alkyl.

U.S. Pat. No. 8,883,438 to Cantley et al., incorporated herein by thisreference, discloses methods of diagnosing a subject having a cellproliferation-related disorder or suspected of having a cellproliferation-related disorder characterized by: (i) the presence,distribution, or level of an isocitrate dehydrogenase 1 enzyme having amutation at residue 97 wherein the glycine residue has been replacedwith an aspartic acid residue (IDH1-G97D), which has 2-hydroxyglutarate(2HG) neoactivity, wherein 2HG neoactivity is the ability to convertα-ketoglutarate to 2-hydroxyglutarate, or (ii) elevated levels of 2HGdue to the presence of IDH1-G97D mutant enzyme having 2HG neoactivity,wherein the method comprises analyzing the presence, distribution, orlevel of 2HG in a tissue, product, or bodily fluid of said subject by achromatographic method, wherein an increased presence, distribution, orlevel of 2HG indicates the presence of the cell proliferation-relateddisorder, thereby diagnosing the subject for the cellproliferation-related disorder. The chromatographic method can be LC-MSor GC-MS. Alternatively, a mutation can be an IDH2-137 mutation. Amethod for treating a malignancy characterized by a mutation in IDH caninclude administration of a cellular structural analog of an α-hydroxyneoactivity product of Formula (S-II):

wherein: (i) each R^(a) and R^(b) is independently hydrogen, a metalion, or a negative charge; (ii) R^(c) is a hydrogen bond donor oracceptor, and can be bound to the carbon chain by a single or doublebond, as indicated by the dashed line; and (iii) n is 0, 1, or 2.Alternatively, an inhibitor of the neoactivity can be administered.

United States Patent Application Publication No. 2014/0100223 by Hussainet al., incorporated herein by this reference, discloses compounds andmethods for the treatment of isocitrate-dehydrogenase-related diseases,including compounds of Formula (S-III):

wherein:

-   -   (i) each n and m is independently 0, 1, 2 or 3;    -   (ii) each p and q is independently 0, 1, 2, 3, 4, 5, 6 or 7;    -   (iii) X₁ is —C(O)N(R_(A))— or —C(S)N(R_(A))—, wherein R_(A) is        independently hydrogen, aliphatic, substituted aliphatic,        heteroaryl, substituted heteroaryl, aryl or substituted aryl;    -   (iv) X₂ is —S— —O—, —S(O)₂— —C(R₂₀)(R₂₁)— or —N(R_(B))—, wherein        R_(B) is independently hydrogen, aliphatic, substituted        aliphatic, heteroaryl, substituted heteroaryl, aryl or        substituted aryl;    -   (v) each R₁ and R₂ is independently hydrogen, halogen,        aliphatic, substituted aliphatic, aryl or substituted aryl;    -   (vi) R₃ is hydrogen, halogen, aliphatic, substituted aliphatic,        aryl or substituted aryl;    -   (vii) each R₁₀, and R₂₈ is independently absent, hydrogen,        halogen, —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —CF₃, —CN, —NO₂, —N₃,        —C(O)OR₂₀, —C(O)R₂₀, —C(O)NR₂₀R₂₁, acyl, alkoxy, substituted        alkoxy, alkylamino, substituted alkylamino, dialkylamino,        substituted dialkylamino, substituted or unsubstituted        alkylthio, substituted or unsubstituted alkylsulfonyl,        aliphatic, substituted aliphatic, aryl or substituted aryl, or        alternatively two of R₁₀ groups together with the atoms to which        they are attached and any intervening atoms may form an        additional optionally substituted, 3, 4, 5, 6 or 7 membered        ring, wherein each R₂₀ and R₂₁ is independently hydrogen,        halogen, aliphatic, substituted aliphatic, aryl or substituted        aryl;    -   (viii) each R₁₁ is independently absent, hydrogen, halogen,        —OR₂₀, —SR₂₀, —NR₂₀R₂₁, —CF₃, —CN, —NO₂, —N₃, —C(O)R₂₀,        —C(O)OR₂₀, —C(O)NR₂₀R₂₁, acyl, alkoxy, substituted alkoxy,        alkylamino, substituted alkylamino, dialkylamino, substituted        dialkylamino, substituted or unsubstituted alkylthio,        substituted or unsubstituted alkylsulfonyl, aliphatic,        substituted aliphatic, aryl or substituted aryl, or        alternatively two of R₁₁ groups together with the atoms to which        they are attached and any intervening atoms may form an        additional optionally substituted, 3, 4, 5, 6 or 7 membered        ring; and    -   (ix) Cyl is an optionally substituted aryl or optionally        substituted heteroaryl.

United States Patent Application Publication No. 2014/0094503 by Ma etal., incorporated herein by this reference, disclosesRNA-interference-mediated interference with expression of IDH1,including interference mediated by small nucleic acid molecules such asshort interfering nucleic acid (siNA), short interfering RNA (sRNA),double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA(shRNA) molecules.

United States Patent Application Publication No. 2013/0109643 by Rigginset al., incorporated herein by this reference, discloses methods fortreating various forms of cancer, including a malignant low-gradeglioma, a secondary glioblastoma, a transforming myeloproliferativedisorder (tMPD), and an acute myelogenous leukemia (AML), withglutaminase inhibitors, including, but not limited to:

-   -   (A) glutaminase inhibitors of Formula (S-IV):

wherein X is sulfur or oxygen; R₁ and R₂ are independently selected fromthe group consisting of lower alkyl, lower alkoxyl, aryl, thiophenyl and—(CH₂)_(n)-aryl; wherein n is 0 or 1, and aryl is a monocyclic aromaticor heteroaromatic group, having ring atoms selected from the groupconsisting of carbon, nitrogen, oxygen, and sulfur, and having at mostthree non-carbon ring atoms, which group may be unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of halogen, lower alkyl, lower alkoxyl, amino, lower alkylamino, amino(lower alkyl), or halo(lower alkyl); and

-   -   (B) a compound selected from the group consisting of        6-diazo-5-oxo-L-norleucine, acivicin, N-ethylmaleimide,        p-chloromercuriphenylsulfonate, L-2-amino-4-oxo-5-chloropentoic        acid, azaserine, and        5-(3-bromo-4-(dimethylamino)phenyl)-2,2-dimethyl-2,3,5,6-tetrahydrobenzo[a]phenanthridin-4(1H)-one;        and pharmaceutically acceptable salts thereof; a particularly        preferred compound is        bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide.

MGMT inhibitors are known in the art.

U.S. Pat. No. 8,791,081 to Liu et al., incorporated herein by thisreference, discloses the use of MGMT inhibitors for the treatment ofneoplastic disorders. The MGMT inhibitors can include, but are notlimited to, O⁶-substituted guanine derivatives or glucose conjugatesthereof. Suitable MGMT inhibitors include O⁶-benzylguanine,O⁶-2-fluoropyridinylmethyl guanine, O⁶-3-iodobenzyl guanine,O⁶-4-bromophenylguanine, O⁶-5-iodothenylguanine, O⁶-benzyl-8-oxoguanine,O⁶-(p-chlorobenzyl)guanine, O⁶-(p-methylbenzyl)guanine,O⁶-(p-bromobenzyl)guanine, O⁶-(p-isopropylbenzyl)guanine,O⁶-(3,5-dimethylbenzyl)guanine, O⁶-(p-n-butylbenzyl)guanine,O⁶-(p-hydroxymethybenzyl)guanine, O⁶-benzylhypoxanthine,N²-acetyl-O⁶-benzylguanine, N²-acetyl-O⁶-benzyl-8-oxo-guanine,2-amino-6-(p-methyl-benzyl-thio)purine,2-amino-6-(benzyloxy)-9-[(ethoxycarbonyl)methyl]purine,2-amino-6-(benzyloxy)-9-(pivaloyloxymethyl)purine,2-amino-6-(benzyl-thio)purine, O⁶-benzyl-7,8-dihydro-8-oxoguanine,2,4,5-triamino-6-benzyloxyprimidine,O⁶-benzyl-9-[(3-oxo-5α-androstan-17β-yloxycarbonyl)methyl]guanine,O⁶-benzyl-9-[(3-oxo-4-androsten-17β-yloxycarbonyl)methylguanine], and8-amino-O⁶-benzylguanine, as well as C8-linker-glucose-conjugatesthereof.

Inhibitors of NF-κB-enhanced expression of MGMT are known in the art.

U.S. Pat. No. 8,299,237 to Lavon, incorporated herein by this reference,discloses nucleic acid sequences and modified nucleotides comprisingNF-κB binding sites within the MGMT promoter region that are useful asdecoy molecules for inhibiting NF-κB-enhanced expression of MGMT.Modified nucleotides can include, for example, bicyclic nucleotideanalogs, nucleotide analogs that are intercalator pseudonucleotidemolecules, and peptide analogs of nucleotides with repeatingN-(2-aminoethyl)-glycine units linked by peptide bonds in place ofdeoxyribose or ribose sugar backbones.

When the improvement is made by chemosensitization, thechemosensitization can comprise, but is not limited to, the use ofdianhydrogalactitol or diacetyldianhydrogalactitol as a chemosensitizerin combination with an agent selected from the group consisting of:

-   -   (a) topoisomerase inhibitors;    -   (b) fraudulent nucleosides;    -   (c) fraudulent nucleotides;    -   (d) thymidylate synthetase inhibitors;    -   (e) signal transduction inhibitors;    -   (f) cisplatin or platinum analogs;    -   (g) alkylating agents;    -   (h) anti-tubulin agents;    -   (i) antimetabolites;    -   (j) berberine;    -   (k) apigenin;    -   (l) amonafide;    -   (m) vinca alkaloids;    -   (n) 5-fluorouracil;    -   (o) curcumin;    -   (p) NF-κB inhibitors;    -   (q) rosmarinic acid;    -   (r) mitoguazone; and    -   (s) tetrandrine.

When the improvement is made by chemopotentiation, the chemopotentiationcan comprise, but is not limited to, the use of dianhydrogalactitol ordiacetyldianhydrogalactitol as a chemopotentiator in combination with anagent selected from the group consisting of:

-   -   (a) topoisomerase inhibitors;    -   (b) fraudulent nucleosides;    -   (c) fraudulent nucleotides;    -   (d) thymidylate synthetase inhibitors;    -   (e) signal transduction inhibitors;    -   (f) cisplatin or platinum analogs;    -   (g) alkylating agents;    -   (h) anti-tubulin agents;    -   (i) antimetabolites;    -   (j) berberine;    -   (k) apigenin;    -   (l) amonafide;    -   (m) vinca alkaloids;    -   (n) 5-fluorouracil;    -   (o) curcumin;    -   (p) NF-κB inhibitors;    -   (q) rosmarinic acid;    -   (r) mitoguazone; and    -   (s) tetrandrine.

In one alternative, when the chemopotentiation involveschemopotentiation of an alkylating agent by the activity ofdianhydrogalactitol or diacetyldianhydrogalactitol. the alkylating agentcan be selected from the group consisting of BCNU, BCNU wafers(Gliadel), CCNU, bendamustine (Treanda), and temozolimide (Temodar).

When the improvement is made by post-treatment management, thepost-treatment management can be, but is not limited to, a methodselected from the group consisting of:

-   -   (a) a therapy associated with pain management;    -   (b) administration of an anti-emetic;    -   (c) an anti-nausea therapy;    -   (d) administration of an anti-inflammatory agent;    -   (e) administration of an anti-pyretic agent; and    -   (f) administration of an immune stimulant.

When the improvement is made by alternative medicine/post-treatmentsupport, the alternative medicine/post-treatment support can be, but isnot limited to, a method selected from the group consisting of:

-   -   (a) hypnosis;    -   (b) acupuncture;    -   (c) meditation;    -   (d) a herbal medication created either synthetically or through        extraction; and    -   (e) applied kinesiology.

In one alternative, when the method is a herbal medication createdeither synthetically or through extraction, the herbal medicationcreated either synthetically or through extraction can be selected fromthe group consisting of:

-   -   (a) a NF-κB inhibitor;    -   (b) a natural anti-inflammatory;    -   (c) an immunostimulant;    -   (d) an antimicrobial; and    -   (v) a flavonoid, isoflavone, or flavone.

When the herbal medication created either synthetically or throughextraction is a NF-κB inhibitor, the NF-κB inhibitor can be selectedfrom the group consisting of parthenolide, curcumin, and rosmarinicacid. When the herbal medication created either synthetically or throughextraction is a natural anti-inflammatory, the natural anti-inflammatorycan be selected from the group consisting of rhein and parthenolide.When the herbal medication created either synthetically or throughextraction is an immunostimulant, the immunostimulant can be a productfound in or isolated from Echinacea. When the herbal medication createdeither synthetically or through extraction is an anti-microbial, theanti-microbial can be berberine. When the herbal medication createdeither synthetically or through extraction is a flavonoid or flavone,the flavonoid, isoflavone, or flavone can be selected from the groupconsisting of apigenin, genistein, apigenenin, genistein, genistin,6″-O-malonylgenistin, 6″-O-acetylgenistin, daidzein, daidzin,6″-O-malonyldaidzin, 6″-O-acetylgenistin, glycitein, glycitin,6″-O-malonylglycitin, and 6-O-acetylglycitin.

When the improvement is made by a bulk drug product improvement, thebulk drug product improvement can be, but is not limited to, a bulk drugproduct improvement selected from the group consisting of:

-   -   (a) salt formation;    -   (b) preparation as a homogeneous crystal structure;    -   (c) preparation as a pure isomer;    -   (d) increased purity;    -   (e) preparation with lower residual solvent content; and    -   (f) preparation with lower residual heavy metal content.

When the improvement is made by use of a diluent, the diluent can be,but is not limited to, a diluent selected from the group consisting of:

-   -   (a) an emulsion;    -   (b) dimethylsulfoxide (DMSO);    -   (c) N-methylformamide (NMF)    -   (d) DMF;    -   (e) ethanol;    -   (f) benzyl alcohol;    -   (g) dextrose-containing water for injection;    -   (h) Cremophor;    -   (i) cyclodextrin; and    -   (j) PEG.

When the improvement is made by use of a solvent system, the solventsystem can be, but is not limited to, a solvent system selected from thegroup consisting of:

-   -   (a) an emulsion;    -   (b) dimethylsulfoxide (DMSO);    -   (c) N-methylformamide (NMF)    -   (d) DMF;    -   (e) ethanol;    -   (f) benzyl alcohol;    -   (g) dextrose-containing water for injection;    -   (h) Cremophor;    -   (i) cyclodextrin; and    -   (j) PEG.

When the improvement is made by use of an excipient, the excipient canbe, but is not limited to, an excipient selected from the groupconsisting of: group consisting of:

-   -   (a) mannitol;    -   (b) albumin;    -   (c) EDTA;    -   (d) sodium bisulfite;    -   (e) benzyl alcohol;    -   (f) a carbonate buffer; and    -   (g) a phosphate buffer.

When the improvement is made by use of a dosage form, the dosage formcan be, but is not limited to, a dosage form selected from the groupconsisting of:

-   -   (a) tablets;    -   (b) capsules;    -   (c) topical gels;    -   (d) topical creams;    -   (e) patches;    -   (f) suppositories; and    -   (g) lyophilized dosage fills.

Formulation of pharmaceutical compositions in tablets, capsules, andtopical gels, topical creams or suppositories is well known in the artand is described, for example, in United States Patent ApplicationPublication No. 2004/0023290 by Griffin et al., incorporated herein bythis reference.

Formulation of pharmaceutical compositions as patches such astransdermal patches is well known in the art and is described, forexample, in U.S. Pat. No. 7,728,042 to Eros et al., incorporated hereinby this reference.

Lyophilized dosage fills are also well known in the art. One generalmethod for the preparation of such lyophilized dosage fills, applicableto dianhydrogalactitol and derivatives thereof and todiacetyldianhydrogalactitol and derivatives thereof, comprises thefollowing steps:

(1) Dissolve the drug in water for injection precooled to below 10° C.Dilute to final volume with cold water for injection to yield a 40 mg/mLsolution.

(2) Filter the bulk solution through an 0.2-μm filter into a receivingcontainer under aseptic conditions. The formulation and filtrationshould be completed in 1 hour.

(3) Fill nominal 1.0 mL filtered solution into sterilized glass vials ina controlled target range under aseptic conditions.

(4) After the filling, all vials are placed with rubber stoppersinserted in the “lyophilization position” and loaded in the prechilledlyophilizer. For the lyophilizer, shelf temperature is set at +5° C. andheld for 1 hour; shelf temperature is then adjusted to −5° C. and heldfor one hour, and the condenser, set to −60° C., turned on.

(5) The vials are then frozen to 30° C. or below and held for no lessthan 3 hours, typically 4 hours.

(6) Vacuum is then turned on, the shelf temperature is adjusted to −5°C., and primary drying is performed for 8 hours; the shelf temperatureis again adjusted to −5° C. and drying is carried out for at least 5hours.

(7) Secondary drying is started after the condenser (set at −60° C.) andvacuum are turned on. In secondary drying, the shelf temperature iscontrolled at +5° C. for 1 to 3 hours, typically 1.5 hours, then at 25°C. for 1 to 3 hours, typically 1.5 hours, and finally at 35-40° C. forat least 5 hours, typically for 9 hours, or until the product iscompletely dried.

(8) Break the vacuum with filtered inert gas (e.g., nitrogen). Stopperthe vials in the lyophilizer.

(9) Vials are removed from the lyophilizer chamber and sealed withaluminum flip-off seals. All vials are visually inspected and labeledwith approved labels.

When the improvement is made by use of dosage kits and packaging, thedosage kits and packaging can be, but are not limited to, dosage kitsand packaging selected from the group consisting of the use of ambervials to protect from light and the use of stoppers with specializedcoatings to improve shelf-life stability.

When the improvement is made by use of a drug delivery system, the drugdelivery system can be, but is not limited to, a drug delivery systemselected from the group consisting of:

-   -   (a) nanocrystals;    -   (b) bioerodible polymers;    -   (c) liposomes;    -   (d) slow release injectable gels; and    -   (e) microspheres.

Nanocrystals are described in U.S. Pat. No. 7,101,576 to Hovey et al.,incorporated herein by this reference.

Bioerodible polymers are described in U.S. Pat. No. 7,318,931 to Okumuet al., incorporated herein by this reference. A bioerodible polymerdecomposes when placed inside an organism, as measured by a decline inthe molecular weight of the polymer over time. Polymer molecular weightscan be determined by a variety of methods including size exclusionchromatography (SEC), and are generally expressed as weight averages ornumber averages. A polymer is bioerodible if, when in phosphate bufferedsaline (PBS) of pH 7.4 and a temperature of 37° C., its weight-averagemolecular weight is reduced by at least 25% over a period of 6 months asmeasured by SEC. Useful bioerodible polymers include polyesters, such aspoly(caprolactone), poly(glycolic acid), poly(lactic acid), andpoly(hydroxybutryate); polyanhydrides, such as poly(adipic anhydride)and poly(maleic anhydride); polydioxanone; polyamines; polyamides;polyurethanes; polyesteramides; polyorthoesters; polyacetals;polyketals; polycarbonates; polyorthocarbonates; polyphosphazenes;poly(malic acid); poly(amino acids); polyvinylpyrrolidone; poly(methylvinyl ether); poly(alkylene oxalate); poly(alkylene succinate);polyhydroxycellulose; chitin; chitosan; and copolymers and mixturesthereof.

Liposomes are well known as drug delivery vehicles. Liposome preparationis described in European Patent Application Publication No. EP 1332755by Weng et al., incorporated herein by this reference.

Slow release injectable gels are known in the art and are described, forexample, in B. Jeong et al., “Drug Release from Biodegradable InjectableThermosensitive Hydrogel of PEG-PLGA-PEG Triblock Copolymers,” J.Controlled Release 63: 155-163 (2000).

The use of microspheres for drug delivery is known in the art and isdescribed, for example, in H. Okada & H. Taguchi, “BiodegradableMicrospheres in Drug Delivery,” Crit. Rev. Ther. Drug Carrier Sys. 12:1-99 (1995), incorporated herein by this reference.

When the improvement is made by use of a drug conjugate form, the drugconjugate form can be, but is not limited to, a drug conjugate formselected from the group consisting of:

-   -   (a) a polymer system;    -   (b) polylactides;    -   (c) polyglycolides;    -   (d) amino acids;    -   (e) peptides; and    -   (f) multivalent linkers.

Polylactide conjugates are well known in the art and are described, forexample, in R. Tong & C. Cheng, “Controlled Synthesis ofCamptothecin-Polylactide Conjugates and Nanoconjugates,” BioconjugateChem. 21: 111-121 (2010), incorporated by this reference.

Polyglycolide conjugates are also well known in the art and aredescribed, for example, in PCT Patent Application Publication No. WO2003/070823 by Elmaleh et al., incorporated herein by this reference.

Multivalent linkers are known in the art and are described, for example,in United States Patent Application Publication No. 2007/0207952 bySilva et al., incorporated herein by this reference. For example,multivalent linkers can contain a thiophilic group for reaction with areactive cysteine, and multiple nucleophilic groups (such as NH or OH)or electrophilic groups (such as activated esters) that permitattachment of a plurality of biologically active moieties to the linker.

Suitable reagents for cross-linking many combinations of functionalgroups are known in the art. For example, electrophilic groups can reactwith many functional groups, including those present in proteins orpolypeptides. Various combinations of reactive amino acids andelectrophiles are known in the art and can be used. For example,N-terminal cysteines, containing thiol groups, can be reacted withhalogens or maleimides. Thiol groups are known to have reactivity with alarge number of coupling agents, such as alkyl halides, haloacetylderivatives, maleimides, aziridines, acryloyl derivatives, arylatingagents such as aryl halides, and others. These are described in G. T.Hermanson, “Bioconjugate Techniques” (Academic Press, San Diego, 1996),pp. 146-150, incorporated herein by this reference. The reactivity ofthe cysteine residues can be optimized by appropriate selection of theneighboring amino acid residues. For example, a histidine residueadjacent to the cysteine residue will increase the reactivity of thecysteine residue. Other combinations of reactive amino acids andelectrophilic reagents are known in the art. For example, maleimides canreact with amino groups, such as the ε-amino group of the side chain oflysine, particularly at higher pH ranges. Aryl halides can also reactwith such amino groups. Haloacetyl derivatives can react with theimidazolyl side chain nitrogens of histidine, the thioether group of theside chain of methionine, and the .epsilon.-amino group of the sidechain of lysine. Many other electrophilic reagents are known that willreact with the ε-amino group of the side chain of lysine, including, butnot limited to, isothiocyanates, isocyanates, acyl azides,N-hydroxysuccinimide esters, sulfonyl chlorides, epoxides, oxiranes,carbonates, imidoesters, carbodiimides, and anhydrides. These aredescribed in G. T. Hermanson, “Bioconjugate Techniques” (Academic Press,San Diego, 1996), pp. 137-146, incorporated herein by this reference.Additionally, electrophilic reagents are known that will react withcarboxylate side chains such as those of aspartate and glutamate, suchas diazoalkanes and diazoacetyl compounds, carbonyldiimidazole, andcarbodiimides. These are described in G. T. Hermanson, “BioconjugateTechniques” (Academic Press, San Diego, 1996), pp. 152-154, incorporatedherein by this reference. Furthermore, electrophilic reagents are knownthat will react with hydroxyl groups such as those in the side chains ofserine and threonine, including reactive haloalkane derivatives. Theseare described in G. T. Hermanson, “Bioconjugate Techniques,” (AcademicPress, San Diego, 1996), pp. 154-158, incorporated herein by thisreference. In another alternative embodiment, the relative positions ofelectrophile and nucleophile (i.e., a molecule reactive with anelectrophile) are reversed so that the protein has an amino acid residuewith an electrophilic group that is reactive with a nucleophile and thetargeting molecule includes therein a nucleophilic group. This includesthe reaction of aldehydes (the electrophile) with hydroxylamine (thenucleophile), described above, but is more general than that reaction;other groups can be used as electrophile and nucleophile. Suitablegroups are well known in organic chemistry and need not be describedfurther in detail.

Additional combinations of reactive groups for cross-linking are knownin the art. For example, amino groups can be reacted withisothiocyanates, isocyanates, acyl azides, N-hydroxysuccinimide (NHS)esters, sulfonyl chlorides, aldehydes, glyoxals, epoxides, oxiranes,carbonates, alkylating agents, imidoesters, carbodiimides, andanhydrides. Thiol groups can be reacted with haloacetyl or alkyl halidederivatives, maleimides, aziridines, acryloyl derivatives, acylatingagents, or other thiol groups by way of oxidation and the formation ofmixed disulfides. Carboxy groups can be reacted with diazoalkanes,diazoacetyl compounds, carbonyldiimidazole, or carbodiimides. Hydroxylgroups can be reacted with epoxides, oxiranes, carbonyldiimidazole,N,N′-disuccinimidyl carbonate, N-hydroxysuccinimidyl chloroformate,periodate (for oxidation), alkyl halogens, or isocyanates. Aldehyde andketone groups can react with hydrazines, reagents forming Schiff bases,and other groups in reductive amination reactions or Mannichcondensation reactions. Still other reactions suitable for cross-linkingreactions are known in the art. Such cross-linking reagents andreactions are described in G. T. Hermanson, “Bioconjugate Techniques”(Academic Press, San Diego, 1996), incorporated herein by thisreference.

When the improvement is made by use of a compound analog, the compoundanalog can be, but is not limited to, a compound analog selected fromthe group consisting of:

-   -   (a) alteration of side chains to increase or decrease        lipophilicity;    -   (b) addition of an additional chemical functionality to alter a        property selected from the group consisting of reactivity,        electron affinity, and binding capacity; and    -   (c) alteration of salt form.

When the improvement is made by use of a prodrug system, the prodrugsystem can be, but is not limited to, a prodrug system selected from thegroup consisting of:

-   -   (a) the use of enzyme sensitive esters;    -   (b) the use of dimers;    -   (c) the use of Schiff bases;    -   (d) the use of pyridoxal complexes; and    -   (e) the use of caffeine complexes.

The use of prodrug systems is described in T. Jarvinen et al., “Designand Pharmaceutical Applications of Prodrugs” in Drug Discovery Handbook(S. C. Gad, ed., Wiley-Interscience, Hoboken, N.J., 2005), ch. 17, pp.733-796, incorporated herein by this reference. This publicationdescribes the use of enzyme sensitive esters as prodrugs. The use ofdimers as prodrugs is described in U.S. Pat. No. 7,879,896 to Allegrettiet al., incorporated herein by this reference. The use of peptides inprodrugs is described in S. Prasad et al., “Delivering MultipleAnticancer Peptides as a Single Prodrug Using Lysyl-Lysine as a FacileLinker,” J. Peptide Sci. 13: 458-467 (2007), incorporated herein by thisreference. The use of Schiff bases as prodrugs is described in U.S. Pat.No. 7,619,005 to Epstein et al., incorporated herein by this reference.The use of caffeine complexes as prodrugs is described in U.S. Pat. No.6,443,898 to Unger et al., incorporated herein by this reference.

When the improvement is made by use of a multiple drug system, themultiple drug system can be, but is not limited to, a multiple drugsystem selected from the group consisting of:

-   -   (a) use of multi-drug resistance inhibitors;    -   (b) use of specific drug resistance inhibitors;    -   (c) use of specific inhibitors of selective enzymes;    -   (d) use of signal transduction inhibitors;    -   (e) use of repair inhibition; and    -   (f) use of topoisomerase inhibitors with non-overlapping side        effects.

Multi-drug resistance inhibitors are described in U.S. Pat. No.6,011,069 to Inomata et al., incorporated herein by this reference.

Specific drug resistance inhibitors are described in T. Hideshima etal., “The Proteasome Inhibitor PS-341 Inhibits Growth, InducesApoptosis, and Overcomes Drug Resistance in Human Multiple MyelomaCells,” Cancer Res. 61: 3071-3076 (2001), incorporated herein by thisreference.

Repair inhibition is described in N. M. Martin, “DNA Repair Inhibitionand Cancer Therapy,” J. Photochem. Photobiol. B 63: 162-170 (2001),incorporated herein by this reference.

When the improvement is made by biotherapeutic enhancement, thebiotherapeutic enhancement can be performed by use in combination assensitizers/potentiators with a therapeutic agent or technique that canbe, but is not limited to, a therapeutic agent or technique selectedfrom the group consisting of:

-   -   (a) cytokines;    -   (b) lymphokines;    -   (c) therapeutic antibodies;    -   (d) antisense therapies;    -   (e) gene therapies;    -   (f) ribozymes; and    -   (g) RNA interference.

Antisense therapies are described, for example, in B. Weiss et al.,“Antisense RNA Gene Therapy for Studying and Modulating BiologicalProcesses,” Cell. Mol. Life Sci. 55: 334-358 (1999), incorporated hereinby this reference.

Ribozymes are described, for example, in S. Pascolo, “RNA-BasedTherapies” in Drug Discovery Handbook (S. C. Gad, ed.,Wiley-Interscience, Hoboken, N.J., 2005), ch. 27, pp. 1273-1278,incorporated herein by this reference.

RNA interference is described, for example, in S. Pascolo, “RNA-BasedTherapies” in Drug Discovery Handbook (S. C. Gad, ed.,Wiley-Interscience, Hoboken, N.J., 2005), ch. 27, pp. 1278-1283,incorporated herein by this reference.

When the biotherapeutic enhancement is use in combination assensitizers/potentiators with a therapeutic antibody, the therapeuticantibody can be, but is not limited to, a therapeutic antibody selectedfrom the group consisting of bevacizumab (Avastin), rituximab (Rituxan),trastuzumab (Herceptin), and cetuximab (Erbitux).

When the improvement is made by use of biotherapeutic resistancemodulation, the biotherapeutic resistance modulation can be, but is notlimited to, use against tumors resistant to a therapeutic agent ortechnique selected from the group consisting of:

-   -   (a) biological response modifiers;    -   (b) cytokines;    -   (c) lymphokines;    -   (d) therapeutic antibodies;    -   (e) antisense therapies;    -   (f) gene therapies;    -   (g) ribozymes; and    -   (h) RNA interference.

When the biotherapeutic resistance modulation is use against tumorsresistant to therapeutic antibodies, the therapeutic antibody can be,but is not limited to, a therapeutic antibody selected from the groupconsisting of bevacizumab (Avastin), rituximab (Rituxan), trastuzumab(Herceptin), and cetuximab (Erbitux).

When the improvement is made by radiation therapy enhancement, theradiation therapy enhancement can be, but is not limited to, a radiationtherapy enhancement agent or technique selected from the groupconsisting of:

-   -   (a) hypoxic cell sensitizers;    -   (b) radiation sensitizers/protectors;    -   (c) photosensitizers;    -   (d) radiation repair inhibitors;    -   (e) thiol depleters;    -   (f) vaso-targeted agents;    -   (g) DNA repair inhibitors;    -   (h) radioactive seeds;    -   (i) radionuclides;    -   (j) radiolabeled antibodies; and    -   (k) brachytherapy.

Hypoxic cell sensitizers are described in C. C. Ling et al., “The Effectof Hypoxic Cell Sensitizers at Different Irradiation Dose Rates,”Radiation Res. 109: 396-406 (1987), incorporated herein by thisreference. Radiation sensitizers are described in T. S. Lawrence,“Radiation Sensitizers and Targeted Therapies,” Oncology 17 (Suppl. 13)23-28 (2003), incorporated herein by this reference. Radiationprotectors are described in S. B. Vuyyuri et al., “Evaluation ofD-Methionine as a Novel Oral Radiation Protector for Prevention ofMucositis,” Clin. Cancer Res. 14: 2161-2170 (2008), incorporated hereinby this reference. Photosensitizers are described in R. R. Allison & C.H. Sibata, “Oncologic Photodynamic Therapy Photosensitizers: A ClinicalReview,” Photodiagnosis Photodynamic Ther. 7: 61-75 (2010), incorporatedherein by this reference. Radiation repair inhibitors and DNA repairinhibitors are described in M. Hingorani et al., “Evaluation of Repairof Radiation-Induced DNA Damage Enhances Expression fromReplication-Defective Adenoviral Vectors,” Cancer Res. 68: 9771-9778(2008), incorporated herein by this reference. Thiol depleters aredescribed in K. D. Held et al., “Postirradiation Sensitization ofMammalian Cells by the Thiol-Depleting Agent Dimethyl Fumarate,”Radiation Res. 127: 75-80 (1991), incorporated herein by this reference.Vaso-targeted agents are described in A. L. Seynhaeve et al., “TumorNecrosis Factor α Mediates Homogeneous Distribution of Liposomes inMurine Melanoma that Contributes to a Better Tumor Response,” CancerRes. 67: 9455-9462 (2007).

When the improvement is by use of a novel mechanism of action, the novelmechanism of action can be, but is not limited to, a novel mechanism ofaction that is a therapeutic interaction with a target or mechanismselected from the group consisting of:

-   -   (a) inhibitors of poly-ADP ribose polymerase;    -   (b) agents that affect vasculature or vasodilation;    -   (c) oncogenic targeted agents;    -   (d) signal transduction inhibitors;    -   (e) EGFR inhibition;    -   (f) protein kinase C inhibition;    -   (g) phospholipase C downregulation;    -   (h) Jun downregulation;    -   (i) histone genes;    -   (j) VEGF;    -   (k) ornithine decarboxylase;    -   (l) ubiquitin C;    -   (m) Jun D;    -   (n) v-Jun;    -   (o) GPCRs;    -   (p) protein kinase A;    -   (q) protein kinases other than protein kinase A;    -   (r) prostate specific genes;    -   (s) telomerase; and    -   (t) histone deacetylase.

EGFR inhibition is described in G. Giaccone & J. A. Rodriguez, “EGFRInhibitors: What Have We Learned from the Treatment of Lung Cancer,”Nat. Clin. Pract. Oncol. 11: 554-561 (2005), incorporated herein by thisreference. Protein kinase C inhibition is described in N. C. Swannie &S. B. Kaye, “Protein Kinase C Inhibitors,” Curr. Oncol. Rep. 4: 37-46(2002), incorporated herein by this reference. Phospholipase Cdownregulation is described in A. M. Martelli et al., “PhosphoinositideSignaling in Nuclei of Friend Cells: Phospholipase C β Downregulation IsRelated to Cell Differentiation,” Cancer Res. 54: 2536-2540 (1994),incorporated herein by this reference. Downregulation of Jun(specifically, c-Jun) is described in A. A. P. Zada et al.,“Downregulation of c-Jun Expression and Cell Cycle Regulatory Moleculesin Acute Myeloid Leukemia Cells Upon CD44 Ligation,” Oncogene 22:2296-2308 (2003), incorporated herein by this reference. The role ofhistone genes as a target for therapeutic intervention is described inB. Calabretta et al., “Altered Expression of G1-Specific Genes in HumanMalignant Myeloid Cells,” Proc. Natl. Acad. Sci. USA 83: 1495-1498(1986), incorporated herein by this reference. The role of VEGF as atarget for therapeutic intervention is described in A. Zielke et al.,“VEGF-Mediated Angiogenesis of Human Pheochromocytomas Is Associated toMalignancy and Inhibited by anti-VEGF Antibodies in ExperimentalTumors,” Surgery 132: 1056-1063 (2002), incorporated herein by thisreference. The role of ornithine decarboxylase as a target fortherapeutic intervention is described in J. A. Nilsson et al.,“Targeting Ornithine Decarboxylase in Myc-Induced LymphomagenesisPrevents Tumor Formation,” Cancer Cell 7: 433-444 (2005), incorporatedherein by this reference. The role of ubiquitin C as a target fortherapeutic intervention is described in C. Aghajanian et al., “A PhaseI Trial of the Novel Proteasome Inhibitor PS341 in Advanced Solid TumorMalignancies,” Clin. Cancer Res. 8: 2505-2511 (2002), incorporatedherein by this reference. The role of Jun D as a target for therapeuticintervention is described in M. M. Caffarel et al., “JunD Is Involved inthe Antiproliferative Effect of Δ⁹-Tetrahydrocannibinol on Human BreastCancer Cells,” Oncogene 27: 5033-5044 (2008), incorporated herein bythis reference. The role of v-Jun as a target for therapeuticintervention is described in M. Gao et al., “Differential andAntagonistic Effects of v-Jun and c-Jun,” Cancer Res. 56: 4229-4235(1996), incorporated herein by this reference. The role of proteinkinase A as a target for therapeutic intervention is described in P. C.Gordge et al., “Elevation of Protein Kinase A and Protein Kinase C inMalignant as Compared With Normal Breast Tissue,” Eur. J. Cancer 12:2120-2126 (1996), incorporated herein by this reference. The role oftelomerase as a target for therapeutic intervention is described in E.K. Parkinson et al., “Telomerase as a Novel and Potentially SelectiveTarget for Cancer Chemotherapy,” Ann. Med. 35: 466-475 (2003),incorporated herein by this reference. The role of histone deacetylaseas a target for therapeutic intervention is described in A. Melnick & J.D. Licht, “Histone Deacetylases as Therapeutic Targets in HematologicMalignancies,” Curr. Opin. Hematol. 9: 322-332 (2002), incorporatedherein by this reference.

When the improvement is made by use of selective target cell populationtherapeutics, the use of selective target cell population therapeuticscan be, but is not limited to, a use selected from the group consistingof:

-   -   (a) use against radiation sensitive cells;    -   (b) use against radiation resistant cells;    -   (c) use against energy depleted cells; and    -   (d) use against endothelial cells.

As described above, the present invention also encompasses methods andcompositions to improve the efficacy and/or reduce the side effects ofsuboptimally administered drug therapy of additional therapeutic agents,including, but not limited to, Avastin (bevacizumab), Rituxan(rituximab), Nexavar (sorafenib), dasatinib, nilotinib, Provenge(sipuleucel-T), Tarceva (erlotinib), and Iressa (gefitinib).

Avastin (bevacizumab) has a number of side effects associated withinterference with angiogenesis, including hypertension and increasedrisk of bleeding. This suggests possible use with antihypertensives,administration of platelets, or agents to improve wound healing.

Rituxan (rituximab) has side effects that include cardiac arrest,infections, including viral infections and hepatitis B reactivation,progressive multifocal encephalopathy, and tumor lysis syndrome. Thissuggests possible use with anti-virals, antibiotics, probenecid (totreat hyperuricemia).

Nexavar (sorafenib) has side effects that include skin rash, skinreactions, diarrhea, and hypertension. This suggests possible use withantihypertensives or anti-inflammatory agents.

Dasatinib has side effects that include neutropenia, myelosuppression,pleural effusions, headache, diarrhea, and peripheral edema. Thissuggests possible use with anti-inflammatory agents or agents thatpromote immune function. Dasatinib has the property that patients withthe T315L mutation in BCR/ABL show resistance to dasatinib. Thissuggests genotypic analysis of patients to whom dasatinib might beadministered.

Nilotinib has side effects that include possible heart complications.Nilotinib also has the property that patients with the T315L mutation inBCR/ABL show resistance to nilotinib. This suggests genotypic analysisof patients to whom nilotinib might be administered.

Provenge (sipuleucel-T) has side effects that include chills, fever,fatigue, nausea, headache, and rare cardiovascular events. This suggestspossible use with anti-inflammatory agents, anti-nausea agents, andanti-emetics.

Tarceva (erlotinib) has side effects that include rash, diarrhea, lossof appetite, fatigue, and interstitial pneumonitis. This suggestspossible use with anti-inflammatory agents and anti-diarrhea agents.Tarceva only works with patients that have an EGFR mutation, whichsuggests genotypic analysis of patents to whom Tarceva might beadministered. Additionally, Tarceva has been found to be a potentinhibitor of the JAK2V617F mutant of the JAK2 tyrosine kinase, and thismutation has been found to exist in most patients with polycythemia veraand many patients with other myeloproliferative disorders, includingidiopathic myelofibrosis and essential thrombocythemia.

Iressa (gefitinib) is also an EGFR inhibitor, and thus its mechanism ofaction is similar to Tarceva. Similarly, this works with patients thathave an EGFR mutation. This drug is particularly used in some types ofnon-small-cell lung cancer, including adenocarcinoma. Side effectsinclude acne, diarrhea, nausea, vomiting, anorexia, stomatitis,interstitial lung disease, and other effects. Again, this suggests usewith anti-inflammatory agents, anti-diarrhea agents, and anti-emetics.

Another aspect of the present invention is a composition to improve theefficacy and/or reduce the side effects of suboptimally administereddrug therapy comprising an alternative selected from the groupconsisting of:

-   -   (i) a therapeutically effective quantity of a modified        therapeutic agent or a derivative, analog, or prodrug of a        therapeutic agent or modified therapeutic agent, wherein the        modified therapeutic agent or the derivative, analog or prodrug        of the therapeutic agent or modified therapeutic agent possesses        increased therapeutic efficacy or reduced side effects as        compared with an unmodified therapeutic agent;    -   (ii) a composition comprising:        -   (a) a therapeutically effective quantity of a therapeutic            agent, a modified therapeutic agent or a derivative, analog,            or prodrug of a therapeutic agent or modified therapeutic            agent; and        -   (b) at least one additional therapeutic agent, therapeutic            agent subject to chemosensitization, therapeutic agent            subject to chemopotentiation, diluent, excipient, solvent            system, or drug delivery system, wherein the composition            possesses increased therapeutic efficacy or reduced side            effects as compared with an unmodified therapeutic agent;    -   (iii) a therapeutically effective quantity of a therapeutic        agent, a modified therapeutic agent, or a derivative, analog, or        prodrug of a therapeutic agent or modified therapeutic agent        that is incorporated into a dosage form, wherein the therapeutic        agent, the modified therapeutic agent, or the derivative,        analog, or prodrug of a therapeutic agent or modified        therapeutic agent incorporated into the dosage form possesses        increased therapeutic efficacy or reduced side effects as        compared with an unmodified therapeutic agent;    -   (iv) a therapeutically effective quantity of a therapeutic        agent, a modified therapeutic agent, or a derivative, analog, or        prodrug of a therapeutic agent or modified therapeutic agent        that is incorporated into a dosage kit and packaging, wherein        the therapeutic agent, the modified therapeutic agent, or the        derivative, analog, or prodrug of a therapeutic agent or        modified therapeutic agent incorporated into the dosage kit and        packaging possesses increased therapeutic efficacy or reduced        side effects as compared with an unmodified therapeutic agent;        and    -   (v) a therapeutically effective quantity of a therapeutic agent,        a modified therapeutic agent, or a derivative, analog, or        prodrug of a therapeutic agent or modified therapeutic agent        that is subjected to a bulk drug product improvement, wherein        the therapeutic agent, the modified therapeutic agent, or the        derivative, analog, or prodrug of a therapeutic agent or        modified therapeutic agent subject to the bulk drug product        improvement possesses increased therapeutic efficacy or reduced        side effects as compared with an unmodified therapeutic agent.

Typically, the composition possesses increased efficacy or reduced sideeffects for cancer therapy. Typically, the unmodified therapeutic agentis dianhydrogalactitol or diacetyldianhydrogalactitol, as describedabove. Alternatively, the unmodified therapeutic agent can be selectedfrom the group consisting of Avastin (bevacizumab), Rituxan (rituximab),Nexavar (sorafenib), dasatinib, nilotinib, Provenge (sipuleucel-T),Tarceva (erlotinib), and Iressa (gefitinib).

In one alternative, the composition comprises a drug combinationcomprising:

-   -   (i) dianhydrogalactitol; and    -   (ii) an additional therapeutic agent selected from the group        consisting of:        -   (a) topoisomerase inhibitors;        -   (b) fraudulent nucleosides;        -   (c) fraudulent nucleotides;        -   (d) thymidylate synthetase inhibitors;        -   (e) signal transduction inhibitors;        -   (f) cisplatin or platinum analogs;        -   (g) alkylating agents;        -   (h) anti-tubulin agents;        -   (i) antimetabolites;        -   (j) berberine;        -   (k) apigenin;        -   (l) amonafide;        -   (m) vinca alkaloids;        -   (n) 5-fluorouracil;        -   (o) curcumin;        -   (p) NF-κB inhibitors;        -   (q) rosmarinic acid;        -   (r) mitoguazone;        -   (s) tetrandrine; and        -   (t) an inhibitor of mutant isocitrate dehydrogenase (IDH);        -   (u) a MGMT inhibitor; and        -   (v) an agent that inhibits NF-κB-enhanced expression of            MGMT.

In another alternative of a composition according to the presentinvention, the composition can comprise a drug combination comprising:

-   -   (i) diacetyldianhydrogalactitol; and    -   (ii) an additional therapeutic agent selected from the group        consisting of:        -   (a) topoisomerase inhibitors;        -   (b) fraudulent nucleosides;        -   (c) fraudulent nucleotides;        -   (d) thymidylate synthetase inhibitors;        -   (e) signal transduction inhibitors;        -   (f) cisplatin or platinum analogs;        -   (g) alkylating agents;        -   (h) anti-tubulin agents;        -   (i) antimetabolites;        -   (j) berberine;        -   (k) apigenin;        -   (l) amonafide;        -   (m) vinca alkaloids;        -   (n) 5-fluorouracil;        -   (o) curcumin;        -   (p) NF-κB inhibitors;        -   (q) rosmarinic acid;        -   (r) mitoguazone;        -   (s) tetrandrine;        -   (t) an inhibitor of mutant isocitrate dehydrogenase (IDH);        -   (u) a MGMT inhibitor; and        -   (v) an agent that inhibits NF-κB-enhanced expression of            MGMT.

In these alternatives, when the additional therapeutic agent is analkylating agent, the alkylating agent can be, but is not limited to, analkylating agent selected from the group consisting of BCNU, BCNUwafers, CCNU, bendamustine (Treanda), and temozolomide (Temodar).

In another alternative, the composition comprises:

-   -   (i) dianhydrogalactitol; and    -   (ii) a therapeutic agent subject to chemosensitization selected        from the group consisting of:        -   (a) topoisomerase inhibitors;        -   (b) fraudulent nucleosides;        -   (c) fraudulent nucleotides;        -   (d) thymidylate synthetase inhibitors;        -   (e) signal transduction inhibitors;        -   (f) cisplatin or platinum analogs;        -   (g) alkylating agents;        -   (h) anti-tubulin agents;        -   (i) antimetabolites;        -   (j) berberine;        -   (k) apigenin;        -   (l) amonafide;        -   (m) vinca alkaloids;        -   (n) 5-fluorouracil;        -   (o) curcumin;        -   (p) NF-κB inhibitors;        -   (q) rosmarinic acid;        -   (r) mitoguazone; and        -   (s) tetrandrine;            wherein the dianhydrogalactitol acts as a chemosensitizer.

In yet another alternative, the composition can comprise:

-   -   (i) diacetyldianhydrogalactitol; and    -   (ii) a therapeutic agent subject to chemosensitization selected        from the group consisting of:        -   (a) topoisomerase inhibitors;        -   (b) fraudulent nucleosides;        -   (c) fraudulent nucleotides;        -   (d) thymidylate synthetase inhibitors;        -   (e) signal transduction inhibitors;        -   (f) cisplatin or platinum analogs;        -   (g) alkylating agents;        -   (h) anti-tubulin agents;        -   (i) antimetabolites;        -   (j) berberine;        -   (k) apigenin;        -   (l) amonafide;        -   (m) vinca alkaloids;        -   (n) 5-fluorouracil;        -   (o) curcumin;        -   (p) NF-κB inhibitors;        -   (q) rosmarinic acid;        -   (r) mitoguazone; and        -   (s) tetrandrine;            wherein the diacetyldianhydrogalactitol acts as a            chemosensitizer.

In still another alternative, the composition comprises:

-   -   (i) dianhydrogalactitol; and    -   (ii) a therapeutic agent subject to chemopotentiation selected        from the group consisting of:        -   (a) topoisomerase inhibitors;        -   (b) fraudulent nucleosides;        -   (c) fraudulent nucleotides;        -   (d) thymidylate synthetase inhibitors;        -   (e) signal transduction inhibitors;        -   (f) cisplatin or platinum analogs;        -   (g) alkylating agents;        -   (h) anti-tubulin agents;        -   (i) antimetabolites;        -   (j) berberine;        -   (k) apigenin;        -   (l) amonafide;        -   (m) vinca alkaloids;        -   (n) 5-fluorouracil;        -   (o) curcumin;        -   (p) NF-κB inhibitors;        -   (q) rosmarinic acid;        -   (r) mitoguazone;        -   (s) tetrandrine; and        -   (t) biotherapeutics;            wherein the dianhydrogalactitol acts as a chemopotentiator.

In yet another alternative, the composition comprises:

-   -   (i) diacetyldianhydrogalactitol; and    -   (ii) a therapeutic agent subject to chemopotentiation selected        from the group consisting of:        -   (a) topoisomerase inhibitors;        -   (b) fraudulent nucleosides;        -   (c) fraudulent nucleotides;        -   (d) thymidylate synthetase inhibitors;        -   (e) signal transduction inhibitors;        -   (f) cisplatin or platinum analogs;        -   (g) alkylating agents;        -   (h) anti-tubulin agents;        -   (i) antimetabolites;        -   (j) berberine;        -   (k) apigenin;        -   (l) amonafide;        -   (m) vinca alkaloids;        -   (n) 5-fluorouracil;        -   (o) curcumin;        -   (p) NF-κB inhibitors;        -   (q) rosmarinic acid;        -   (r) mitoguazone;        -   (s) tetrandrine; and        -   (t) biotherapeutics;            wherein the diacetyldianhydrogalactitol acts as a            chemopotentiator.

In these alternatives, wherein the additional therapeutic agent is abiotherapeutic, the biotherapeutic can be, but is not limited to, abiotherapeutic selected from the group consisting of Avastin, Herceptin,Rituxan, and Erbitux.

In yet another alternative, the therapeutic agent is dianhydrogalactitolor diacetyldianhydrogalactitol and the dianhydrogalactitol ordiacetyldianhydrogalactitol is subjected to a bulk drug productimprovement, wherein the bulk drug product improvement is selected fromthe group consisting of:

-   -   (a) salt formation;    -   (b) preparation as a homogeneous crystal structure;    -   (c) preparation as a pure isomer;    -   (d) increased purity;    -   (e) preparation with lower residual solvent content; and    -   (f) preparation with lower residual heavy metal content.

In still another alternative, the therapeutic agent isdianhydrogalactitol or diacetyldianhydrogalactitol and the compositioncomprises a diluent, wherein the diluent is selected from the groupconsisting of:

-   -   (a) an emulsion;    -   (b) dimethylsulfoxide (DMSO);    -   (c) N-methylformamide (NMF)    -   (d) DMF;    -   (e) ethanol;    -   (f) benzyl alcohol;    -   (g) dextrose-containing water for injection;    -   (h) Cremophor;    -   (i) cyclodextrin; and    -   (j) PEG.

In still another alternative, the therapeutic agent isdianhydrogalactitol or diacetyldianhydrogalactitol and the compositioncomprises a solvent system, wherein the solvent system is selected fromthe group consisting of:

-   -   (a) an emulsion;    -   (b) dimethylsulfoxide (DMSO);    -   (c) N-methylformamide (NMF)    -   (d) DMF;    -   (e) ethanol;    -   (f) benzyl alcohol;    -   (g) dextrose-containing water for injection;    -   (h) Cremophor;    -   (i) cyclodextrin; and    -   (j) PEG.

In yet another alternative, the therapeutic agent is dianhydrogalactitolor diacetyldianhydrogalactitol and the composition comprises anexcipient, wherein the excipient is selected from the group consistingof:

-   -   (a) mannitol;    -   (b) albumin;    -   (c) EDTA;    -   (d) sodium bisulfite;    -   (e) benzyl alcohol;    -   (f) a carbonate buffer; and    -   (g) a phosphate buffer.

In still another alternative, the therapeutic agent isdianhydrogalactitol or diacetyldianhydrogalactitol and thedianhydrogalactitol or diacetyldianhydrogalactitol is incorporated intoa dosage form selected from the group consisting of:

-   -   (a) tablets;    -   (b) capsules;    -   (c) topical gels;    -   (d) topical creams;    -   (e) patches;    -   (f) suppositories; and    -   (g) lyophilized dosage fills.

In yet another alternative, the therapeutic agent is dianhydrogalactitolor diacetyldianhydrogalactitol and the dianhydrogalactitol ordiacetyldianhydrogalactitol is incorporated into a dosage kit andpackaging selected from the group consisting of amber vials to protectfrom light and stoppers with specialized coatings to improve shelf-lifestability.

In still another alternative, the therapeutic agent isdianhydrogalactitol or diacetyldianhydrogalactitol and the compositioncomprises a drug delivery system selected from the group consisting of:

-   -   (a) nanocrystals;    -   (b) bioerodible polymers;    -   (c) liposomes;    -   (d) slow release injectable gels; and    -   (e) microspheres.

In still another alternative, the therapeutic agent isdianhydrogalactitol or diacetyldianhydrogalactitol and thedianhydrogalactitol or diacetyldianhydrogalactitol is present in thecomposition in a drug conjugate form selected from the group consistingof:

-   -   (a) a polymer system;    -   (b) polylactides;    -   (c) polyglycolides;    -   (d) amino acids;    -   (e) peptides; and    -   (f) multivalent linkers.

In yet another alternative, the therapeutic agent is a modifieddianhydrogalactitol or a modified diacetyldianhydrogalactitol and themodification is selected from the group consisting of:

-   -   (a) alteration of side chains to increase or decrease        lipophilicity;    -   (b) addition of an additional chemical functionality to alter a        property selected from the group consisting of reactivity,        electron affinity, and binding capacity; and    -   (c) alteration of salt form.

In still another alternative, the therapeutic agent isdianhydrogalactitol or diacetyldianhydrogalactitol and thedianhydrogalactitol or diacetyldianhydrogalactitol is in the form of aprodrug system, wherein the prodrug system is selected from the groupconsisting of:

-   -   (a) the use of enzyme sensitive esters;    -   (b) the use of dimers;    -   (c) the use of Schiff bases;    -   (d) the use of pyridoxal complexes; and    -   (e) the use of caffeine complexes.

In yet another alternative, the therapeutic agent is dianhydrogalactitolor diacetyldianhydrogalactitol and the composition further comprises atleast one additional therapeutic agent to form a multiple drug system,wherein the at least one additional therapeutic agent is selected fromthe group consisting of:

-   -   (a) an inhibitor of multi-drug resistance;    -   (b) a specific drug resistance inhibitor;    -   (c) a specific inhibitor of a selective enzyme;    -   (d) a signal transduction inhibitor;    -   (e) an inhibitor of a repair enzyme; and    -   (f) a topoisomerase inhibitor with non-overlapping side effects.

When a pharmaceutical composition according to the present inventionincludes a prodrug, prodrugs and active metabolites of a compound may beidentified using routine techniques known in the art. See, e.g.,Bertolini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan et al., J.Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev. Res., 34, 220-230(1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard,Design of Prodrugs (Elsevier Press 1985); Larsen, Design and Applicationof Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al.,eds., Harwood Academic Publishers, 1991); Dear et al., J. Chromatogr. B,748, 281-293 (2000); Spraul et al., J. Pharmaceutical & BiomedicalAnalysis, 10, 601-605 (1992); and Prox et al., Xenobiol., 3, 103-112(1992).

When the pharmacologically active compound in a pharmaceuticalcomposition according to the present invention possesses a sufficientlyacidic, a sufficiently basic, or both a sufficiently acidic and asufficiently basic functional group, these group or groups canaccordingly react with any of a number of inorganic or organic bases,and inorganic and organic acids, to form a pharmaceutically acceptablesalt. Exemplary pharmaceutically acceptable salts include those saltsprepared by reaction of the pharmacologically active compound with amineral or organic acid or an inorganic base, such as salts includingsulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, β-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates. If the pharmacologicallyactive compound has one or more basic functional groups, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and the like, or with an organicacid, such as acetic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, a pyranosidyl acid, such as glucuronic acid orgalacturonic acid, an alpha-hydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. Ifthe pharmacologically active compound has one or more acidic functionalgroups, the desired pharmaceutically acceptable salt may be prepared byany suitable method available in the art, for example, treatment of thefree acid with an inorganic or organic base, such as an amine (primary,secondary or tertiary), an alkali metal hydroxide or alkaline earthmetal hydroxide, or the like. Illustrative examples of suitable saltsinclude organic salts derived from amino acids, such as glycine andarginine, ammonia, primary, secondary, and tertiary amines, and cyclicamines, such as piperidine, morpholine and piperazine, and inorganicsalts derived from sodium, calcium, potassium, magnesium, manganese,iron, copper, zinc, aluminum and lithium.

In the case of agents that are solids, it is understood by those skilledin the art that the inventive compounds and salts may exist in differentcrystal or polymorphic forms, all of which are intended to be within thescope of the present invention and specified formulas.

The amount of a given pharmacologically active agent that is included ina unit dose of a pharmaceutical composition according to the presentinvention will vary depending upon factors such as the particularcompound, disease condition and its severity, the identity (e.g.,weight) of the subject in need of treatment, but can nevertheless beroutinely determined by one skilled in the art. Typically, suchpharmaceutical compositions include a therapeutically effective quantityof the pharmacologically active agent and an inert pharmaceuticallyacceptable carrier or diluent. Typically, these compositions areprepared in unit dosage form appropriate for the chosen route ofadministration, such as oral administration or parenteraladministration. A pharmacologically active agent as described above canbe administered in conventional dosage form prepared by combining atherapeutically effective amount of such a pharmacologically activeagent as an active ingredient with appropriate pharmaceutical carriersor diluents according to conventional procedures. These procedures mayinvolve mixing, granulating and compressing or dissolving theingredients as appropriate to the desired preparation. Thepharmaceutical carrier employed may be either a solid or liquid.Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar,pectin, acacia, magnesium stearate, stearic acid and the like. Exemplaryof liquid carriers are syrup, peanut oil, olive oil, water and the like.Similarly, the carrier or diluent may include time-delay or time-releasematerial known in the art, such as glyceryl monostearate or glyceryldistearate alone or with a wax, ethylcellulose,hydroxypropylmethylcellulose, methylmethacrylate and the like.

A variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier may vary, but generally will befrom about 25 mg to about 1 g. If a liquid carrier is used, thepreparation will be in the form of syrup, emulsion, soft gelatincapsule, sterile injectable solution or suspension in an ampoule or vialor non-aqueous liquid suspension.

To obtain a stable water-soluble dose form, a pharmaceuticallyacceptable salt of a pharmacologically active agent as described aboveis dissolved in an aqueous solution of an organic or inorganic acid,such as 0.3 M solution of succinic acid or citric acid. If a solublesalt form is not available, the agent may be dissolved in a suitablecosolvent or combinations of cosolvents. Examples of suitable cosolventsinclude, but are not limited to, alcohol, propylene glycol, polyethyleneglycol 300, polysorbate 80, glycerin and the like in concentrationsranging from 0-60% of the total volume. In an exemplary embodiment, acompound of Formula I is dissolved in DMSO and diluted with water. Thecomposition may also be in the form of a solution of a salt form of theactive ingredient in an appropriate aqueous vehicle such as water orisotonic saline or dextrose solution.

It will be appreciated that the actual dosages of the agents used in thecompositions of this invention will vary according to the particularcomplex being used, the particular composition formulated, the mode ofadministration and the particular site, host and disease and/orcondition being treated. Actual dosage levels of the active ingredientsin the pharmaceutical compositions of the present invention can bevaried so as to obtain an amount of the active ingredient which iseffective to achieve the desired therapeutic response for a particularsubject, composition, and mode of administration, without being toxic tothe subject. The selected dosage level depends upon a variety ofpharmacokinetic factors including the activity of the particulartherapeutic agent, the route of administration, the time ofadministration, the rate of excretion of the particular compound beingemployed, the severity of the condition, other health considerationsaffecting the subject, and the status of liver and kidney function ofthe subject. It also depends on the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular therapeutic agent employed, as well as the age, weight,condition, general health and prior medical history of the subject beingtreated, and like factors. Methods for determining optimal dosages aredescribed in the art, e.g., Remington: The Science and Practice ofPharmacy, Mack Publishing Co., 20^(th) ed., 2000. Optimal dosages for agiven set of conditions can be ascertained by those skilled in the artusing conventional dosage-determination tests in view of theexperimental data for an agent. For oral administration, an exemplarydaily dose generally employed is from about 0.001 to about 3000 mg/kg ofbody weight, with courses of treatment repeated at appropriateintervals. In some embodiments, the daily dose is from about 1 to 3000mg/kg of body weight.

Typical daily doses in a patient may be anywhere between about 500 mg toabout 3000 mg, given once or twice daily, e.g., 3000 mg can be giventwice daily for a total dose of 6000 mg. In one embodiment, the dose isbetween about 1000 to about 3000 mg. In another embodiment, the dose isbetween about 1500 to about 2800 mg. In other embodiments, the dose isbetween about 2000 to about 3000 mg.

Plasma concentrations in the subjects may be between about 100 μM toabout 1000 μM. In some embodiments, the plasma concentration may bebetween about 200 μM to about 800 μM. In other embodiments, theconcentration is about 300 μM to about 600 μM. In still otherembodiments the plasma concentration may be between about 400 to about800 μM. Administration of prodrugs is typically dosed at weight levelswhich are chemically equivalent to the weight levels of the fully activeform.

The compositions of the invention may be manufactured using techniquesgenerally known for preparing pharmaceutical compositions, e.g., byconventional techniques such as mixing, dissolving, granulating,dragee-making, levitating, emulsifying, encapsulating, entrapping orlyophilizing. Pharmaceutical compositions may be formulated in aconventional manner using one or more physiologically acceptablecarriers, which may be selected from excipients and auxiliaries thatfacilitate processing of the active compounds into preparations, whichcan be used pharmaceutically.

Proper formulation is dependent upon the route of administration chosen.For injection, the agents of the invention may be formulated intoaqueous solutions, preferably in physiologically compatible buffers suchas Hanks's solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carriersknown in the art. Such carriers enable the compounds of the invention tobe formulated as tablets, pills, dragees, capsules, liquids, gels,syrups, slurries, solutions, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained using a solid excipient in admixture with theactive ingredient (agent), optionally grinding the resulting mixture,and processing the mixture of granules after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients include: fillers such as sugars, including lactose, sucrose,mannitol, or sorbitol; and cellulose preparations, for example, maizestarch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose,or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acidor a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol,and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillerssuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate, and, optionally, stabilizers. In softcapsules, the active agents may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration. For buccal administration, the compositions may take theform of tablets or lozenges formulated in conventional manner.

Pharmaceutical formulations for parenteral administration can includeaqueous solutions or suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil or synthetic fatty acidesters, such as ethyl oleate or triglycerides. Aqueous injectionsuspensions may contain substances which increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension may also contain suitablestabilizers or modulators which increase the solubility ordispersibility of the composition to allow for the preparation of highlyconcentrated solutions, or can contain suspending or dispersing agents.Pharmaceutical preparations for oral use can be obtained by combiningthe pharmacologically active agent with solid excipients, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets ordragee cores. Suitable excipients are, in particular, fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating modulators may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Other ingredients such as stabilizers, for example, antioxidants such assodium citrate, ascorbyl palmitate, propyl gallate, reducing agents,ascorbic acid, vitamin E, sodium bisulfite, butylated hydroxytoluene,BHA, acetylcysteine, monothioglycerol, phenyl-α-naphthylamine, orlecithin can be used. Also, chelators such as EDTA can be used. Otheringredients that are conventional in the area of pharmaceuticalcompositions and formulations, such as lubricants in tablets or pills,coloring agents, or flavoring agents, can be used. Also, conventionalpharmaceutical excipients or carriers can be used. The pharmaceuticalexcipients can include, but are not necessarily limited to, calciumcarbonate, calcium phosphate, various sugars or types of starch,cellulose derivatives, gelatin, vegetable oils, polyethylene glycols andphysiologically compatible solvents. Other pharmaceutical excipients arewell known in the art. Exemplary pharmaceutically acceptable carriersinclude, but are not limited to, any and/or all of solvents, includingaqueous and non-aqueous solvents, dispersion media, coatings,antibacterial and/or antifungal agents, isotonic and/or absorptiondelaying agents, and/or the like. The use of such media and/or agentsfor pharmaceutically active substances is well known in the art. Exceptinsofar as any conventional medium, carrier, or agent is incompatiblewith the active ingredient or ingredients, its use in a compositionaccording to the present invention is contemplated. Supplementary activeingredients can also be incorporated into the compositions, particularlyas described above. For administration of any of the compounds used inthe present invention, preparations should meet sterility, pyrogenicity,general safety, and purity standards as required by the FDA Office ofBiologics Standards or by other regulatory organizations regulatingdrugs.

For administration intranasally or by inhalation, the compounds for useaccording to the present invention are conveniently delivered in theform of an aerosol spray presentation from pressurized packs or anebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator and the like may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit-dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active agents may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension may also contain suitablestabilizers or agents, which increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use. The compounds may also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds may alsobe formulated as a depot preparation. Such long-acting formulations maybe administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example, as an emulsion in an acceptable oil) orion-exchange resins, or as sparingly soluble derivatives, for example,as a sparingly soluble salt.

An exemplary pharmaceutical carrier for hydrophobic compounds is acosolvent system comprising benzyl alcohol, a nonpolar surfactant, awater-miscible organic polymer, and an aqueous phase. The cosolventsystem may be a VPD co-solvent system. VPD is a solution of 3% w/vbenzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.The VPD co-solvent system (VPD:5W) contains VPD diluted 1:1 with a 5%dextrose in water solution. This co-solvent system dissolves hydrophobiccompounds well, and itself produces low toxicity upon systemicadministration. Naturally, the proportions of a co-solvent system may bevaried considerably without destroying its solubility and toxicitycharacteristics. Furthermore, the identity of the co-solvent componentsmay be varied: for example, other low-toxicity nonpolar surfactants maybe used instead of polysorbate 80; the fraction size of polyethyleneglycol may be varied; other biocompatible polymers may replacepolyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars orpolysaccharides may be substituted for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are known examples ofdelivery vehicles or carriers for hydrophobic drugs. Certain organicsolvents such as dimethylsulfoxide also may be employed, althoughusually at the cost of greater toxicity. Additionally, the compounds maybe delivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials have been established and are knownby those skilled in the art. Sustained-release capsules may, dependingon their chemical nature, release the compounds for a few weeks up toover 100 days. Depending on the chemical nature and the biologicalstability of the therapeutic reagent, additional strategies for proteinstabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid- orgel-phase carriers or excipients. Examples of such carriers orexcipients include calcium carbonate, calcium phosphate, sugars,starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols.

A pharmaceutical composition can be administered by a variety of methodsknown in the art. The routes and/or modes of administration varydepending upon the desired results. Depending on the route ofadministration, the pharmacologically active agent may be coated in amaterial to protect the targeting composition or other therapeutic agentfrom the action of acids and other compounds that may inactivate theagent. Conventional pharmaceutical practice can be employed to providesuitable formulations or compositions for the administration of suchpharmaceutical compositions to subjects. Any appropriate route ofadministration can be employed, for example, but not limited to,intravenous, parenteral, intraperitoneal, intravenous, transcutaneous,subcutaneous, intramuscular, intraurethral, or oral administration.Depending on the severity of the malignancy or other disease, disorder,or condition to be treated, as well as other conditions affecting thesubject to be treated, either systemic or localized delivery of thepharmaceutical composition can be used in the course of treatment. Thepharmaceutical composition as described above can be administeredtogether with additional therapeutic agents intended to treat aparticular disease or condition, which may be the same disease orcondition that the pharmaceutical composition is intended to treat,which may be a related disease or condition, or which even may be anunrelated disease or condition.

Pharmaceutical compositions according to the present invention can beprepared in accordance with methods well known and routinely practicedin the art. See, e.g., Remington: The Science and Practice of Pharmacy,Mack Publishing Co., 20^(th) ed., 2000; and Sustained and ControlledRelease Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc.,New York, 1978. Pharmaceutical compositions are preferably manufacturedunder GMP conditions. Formulations for parenteral administration may,for example, contain excipients, sterile water, or saline, polyalkyleneglycols such as polyethylene glycol, oils of vegetable origin, orhydrogenated naphthalenes. Biocompatible, biodegradable lactidepolymers, lactide/glycolide copolymers, orpolyoxyethylene-polyoxypropylene copolymers may be used to control therelease of the compounds. Other potentially useful parenteral deliverysystems for molecules of the invention include ethylene-vinyl acetatecopolymer particles, osmotic pumps, and implantable infusion systems.Formulations for inhalation may contain excipients, for example,lactose, or may be aqueous solutions containing, e.g.,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or can beoily solutions for administration or gels.

Pharmaceutical compositions according to the present invention areusually administered to the subjects on multiple occasions. Intervalsbetween single dosages can be weekly, monthly or yearly. Intervals canalso be irregular as indicated by therapeutic response or otherparameters well known in the art. Alternatively, the pharmaceuticalcomposition can be administered as a sustained release formulation, inwhich case less frequent administration is required. Dosage andfrequency vary depending on the half-life in the subject of thepharmacologically active agent included in a pharmaceutical composition.The dosage and frequency of administration can vary depending on whetherthe treatment is prophylactic or therapeutic. In prophylacticapplications, a relatively low dosage is administered at relativelyinfrequent intervals over a long period of time. Some subjects maycontinue to receive treatment for the rest of their lives. Intherapeutic applications, a relatively high dosage at relatively shortintervals is sometimes required until progression of the disease isreduced or terminated, and preferably until the subject shows partial orcomplete amelioration of symptoms of disease. Thereafter, the subjectcan be administered a prophylactic regime.

For the purposes of the present application, treatment can be monitoredby observing one or more of the improving symptoms associated with thedisease, disorder, or condition being treated, or by observing one ormore of the improving clinical parameters associated with the disease,disorder, or condition being treated, as described above.

Sustained-release formulations or controlled-release formulations arewell-known in the art. For example, the sustained-release orcontrolled-release formulation can be (1) an oral matrixsustained-release or controlled-release formulation; (2) an oralmultilayered sustained-release or controlled-release tablet formulation;(3) an oral multiparticulate sustained-release or controlled-releaseformulation; (4) an oral osmotic sustained-release or controlled-releaseformulation; (5) an oral chewable sustained-release orcontrolled-release formulation; or (6) a dermal sustained-release orcontrolled-release patch formulation.

The pharmacokinetic principles of controlled drug delivery aredescribed, for example, in B. M. Silber et al.,“Pharmacokinetic/Pharmacodynamic Basis of Controlled Drug Delivery” inControlled Drug Delivery: Fundamentals and Applications (J. R. Robinson& V. H. L. Lee, eds, 2d ed., Marcel Dekker, New York, 1987), ch. 5, pp.213-251, incorporated herein by this reference.

One of ordinary skill in the art can readily prepare formulations forcontrolled release or sustained release comprising a pharmacologicallyactive agent according to the present invention by modifying theformulations described above, such as according to principles disclosedin V. H. K. Li et al, “Influence of Drug Properties and Routes of DrugAdministration on the Design of Sustained and Controlled ReleaseSystems” in Controlled Drug Delivery: Fundamentals and Applications (J.R. Robinson & V. H. L. Lee, eds, 2d ed., Marcel Dekker, New York, 1987),ch. 1, pp. 3-94, incorporated herein by this reference. This process ofpreparation typically takes into account physicochemical properties ofthe pharmacologically active agent, such as aqueous solubility,partition coefficient, molecular size, stability, and nonspecificbinding to proteins and other biological macromolecules. This process ofpreparation also takes into account biological factors, such asabsorption, distribution, metabolism, duration of action, the possibleexistence of side effects, and margin of safety, for thepharmacologically active agent. Accordingly, one of ordinary skill inthe art could modify the formulations into a formulation having thedesirable properties described above for a particular application.

U.S. Pat. No. 6,573,292 by Nardella, U.S. Pat. No. 6,921,722 byNardella, U.S. Pat. No. 7,314,886 to Chao et al., and U.S. Pat. No.7,446,122 by Chao et al., which disclose methods of use of variouspharmacologically active agents and pharmaceutical compositions intreating a number of diseases and conditions, including cancer, andmethods of determining the therapeutic effectiveness of suchpharmacologically active agents and pharmaceutical compositions, are allincorporated herein by this reference.

ADVANTAGES OF THE INVENTION

The present invention provides more effective and efficient methods ofusing therapeutic drugs that have previously been evaluated fortreatment of a number of diseases and conditions, especiallyhyperproliferative disorders, but whose evaluations resulted in apremature conclusion of lack of sufficient efficacy or of occurrence ofside effects sufficient to prevent the use of the therapeutic drug. Suchmore effective and efficient methods of therapeutic drugs will improveefficacy, prevent or reduce the occurrence of significant side effects,and will identify categories of patients and situations in which suchdrugs can be effectively employed. These therapeutic drugs include, butare not limited to, dianhydrogalactitol and diacetyldianhydrogalactitol.

Methods according to the present invention possess industrialapplicability for the preparation of a medicament for the treatment of anumber of diseases and conditions, especially hyperproliferativediseases, and compositions according to the present invention possessindustrial applicability as pharmaceutical compositions.

The inventions illustratively described herein can suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising,” “including,” “containing,” etc. shall be read expansivelyand without limitation. Additionally, the terms and expressions employedherein have been used as terms of description and not of limitation, andthere is no intention in the use of such terms and expressions ofexcluding any equivalents of the future shown and described or anyportion thereof, and it is recognized that various modifications arepossible within the scope of the invention claimed. Thus, it should beunderstood that although the present invention has been specificallydisclosed by preferred embodiments and optional features, modificationand variation of the inventions herein disclosed can be resorted bythose skilled in the art, and that such modifications and variations areconsidered to be within the scope of the inventions disclosed herein.The inventions have been described broadly and generically herein. Eachof the narrower species and subgeneric groupings falling within thescope of the generic disclosure also form part of these inventions. Thisincludes the generic description of each invention with a proviso ornegative limitation removing any subject matter from the genus,regardless of whether or not the excised materials specifically residedtherein.

In addition, where features or aspects of an invention are described interms of the Markush group, those schooled in the art will recognizethat the invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. It is also to beunderstood that the above description is intended to be illustrative andnot restrictive. Many embodiments will be apparent to those of in theart upon reviewing the above description. The scope of the inventionshould therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to theappended claims, along with the full scope of equivalents to which suchclaims are entitled. The disclosures of all articles and references,including patent publications, are incorporated herein by reference.

What is claimed is:
 1. A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy, wherein the composition possesses increased efficacy or reduced side effects for cancer therapy, wherein the composition comprises a drug combination comprising: (a) dianhydrogalactitol or diacetyldianhydrogalactitol; and (b) an additional therapeutic agent selected from the group consisting of: (i) topoisomerase inhibitors; (ii) fraudulent nucleosides; (iii) fraudulent nucleotides; (iv) thymidylate synthetase inhibitors; (v) signal transduction inhibitors; (vi) cisplatin or platinum analogs; (vii) alkylating agents; (viii) anti-tubulin agents; (ix) antimetabolites; (x) berberine; (xi) apigenin; (xii) amonafide; (xiii) vinca alkaloids; (xiv) 5-fluorouracil; (xv) curcumin; (xvi) NF-κB inhibitors; (xvii) rosmarinic acid; (xviii) mitoguazone; and (xix) tetrandrine.
 2. A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy, wherein the composition possesses increased efficacy or reduced side effects for cancer therapy, wherein the composition comprises: (a) dianhydrogalactitol or diacetyldianhydrogalactitol; and (b) a therapeutic agent subject to chemosensitization selected from the group consisting of: (i) topoisomerase inhibitors; (ii) fraudulent nucleosides; (iii) fraudulent nucleotides; (iv) thymidylate synthetase inhibitors; (v) signal transduction inhibitors; (vi) cisplatin or platinum analogs; (vii) alkylating agents; (viii) anti-tubulin agents; (ix) antimetabolites; (x) berberine; (xi) apigenin; (xii) amonafide; (xiii) vinca alkaloids; (xiv) 5-fluorouracil; (xv) curcumin; (xvi) NF-κB inhibitors; (xvii) rosmarinic acid; (xviii) mitoguazone; and (xix) tetrandrine; wherein the dianhydrogalactitol or diacetyldianhydrogalactitol acts as a chemosensitizer.
 3. A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy, wherein the composition possesses increased efficacy or reduced side effects for cancer therapy, wherein the composition comprises: (a) dianhydrogalactitol or di acetyl dianhydrogalactitol; and (b) a therapeutic agent subject to chemopotentiation selected from the group consisting of: (i) topoisomerase inhibitors; (ii) fraudulent nucleosides; (iii) fraudulent nucleotides; (iv) thymidylate synthetase inhibitors; (v) signal transduction inhibitors; (vi) cisplatin or platinum analogs; (vii) alkylating agents; (viii) anti-tubulin agents; (ix) antimetabolites; (x) berberine; (xi) apigenin; (xii) amonafide; (xiii) vinca alkaloids; (xiv) 5-fluorouracil; (xv) curcumin; (xvi) NF-κB inhibitors; (xvii) rosmarinic acid; (xviii) mitoguazone; (xix) tetrandrine; and (xx) biotherapeutics; wherein the dianhydrogalactitol or diacetyldianhydrogalactitol acts as a chemopotentiator.
 4. A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy, wherein the composition possesses increased efficacy or reduced side effects for cancer therapy, wherein the composition comprises a therapeutic agent that is dianhydrogalactitol or diacetyldianhydrogalactitol and the composition also comprises a diluent, wherein the diluent is selected from the group consisting of: (i) an emulsion; (ii) N-methylformamide (NMF); (iii) DMF; (iv) ethanol; (v) benzyl alcohol; (vi) dextrose-containing water for injection; (vii) Cremophor; (viii) cyclodextrin; and (ix) PEG.
 5. A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy, wherein the composition possesses increased efficacy or reduced side effects for cancer therapy, wherein the composition comprises a therapeutic agent that is dianhydrogalactitol or diacetyldianhydrogalactitol and the composition also comprises a solvent system, wherein the solvent system is selected from the group consisting of: (i) an emulsion; (ii) N-methylformamide (NMF); (iii) DMF; (iv) ethanol; (v) benzyl alcohol; (vi) dextrose-containing water for injection; (vii) Cremophor; (viii) cyclodextrin; and (ix) PEG.
 6. A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy, wherein the composition possesses increased efficacy or reduced side effects for cancer therapy, wherein the composition comprises a therapeutic agent that is dianhydrogalactitol or diacetyldianhydrogalactitol and the composition also comprises an excipient, wherein the excipient is selected from the group consisting of: (i) mannitol; (ii) albumin; (iii) EDTA; (iv) sodium bisulfite; (v) benzyl alcohol; (vi) a carbonate buffer; and (vii) a phosphate buffer.
 7. A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy, wherein the composition possesses increased efficacy or reduced side effects for cancer therapy, wherein the composition comprises a therapeutic agent that is dianhydrogalactitol or diacetyldianhydrogalactitol and wherein the dianhydrogalactitol or diacetyldianhydrogalactitol is incorporated into a dosage form selected from the group consisting of: (i) tablets; (ii) capsules; (iii) topical gels; (iv) topical creams; (v) patches; (vi) suppositories; and (vii) lyophilized dosage fills.
 8. A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy, wherein the composition possesses increased efficacy or reduced side effects for cancer therapy, wherein the composition comprises a therapeutic agent that is dianhydrogalactitol or diacetyldianhydrogalactitol and the composition also comprises a drug delivery system selected from the group consisting of: (i) nanocrystals; (ii) bioerodible polymers; (iii) liposomes; (iv) slow release injectable gels; and (v) microspheres.
 9. A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy, wherein the composition possesses increased efficacy or reduced side effects for cancer therapy, wherein the composition comprises a therapeutic agent that is dianhydrogalactitol or diacetyldianhydrogalactitol and the dianhydrogalactitol or diacetyldianhydrogalactitol is present in the composition in a drug conjugate form selected from the group consisting of: (i) a polymer system; (ii) polylactides; (iii) polyglycolides; (iv) amino acids; (v) peptides; and (vi) multivalent linkers.
 10. A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy, wherein the composition possesses increased efficacy or reduced side effects for cancer therapy, wherein the composition comprises a therapeutic agent that is dianhydrogalactitol or diacetyldianhydrogalactitol and the dianhydrogalactitol or diacetyldianhydrogalactitol is in the form of a prodrug system, wherein the prodrug system is selected from the group consisting of: (i) the use of enzyme sensitive esters; (ii) the use of dimers; (iii) the use of Schiff bases; (iv) the use of pyridoxal complexes; and (v) the use of caffeine complexes. 